Trial Outcomes & Findings for Lenalidomide and Rituximab in the Treatment of Relapsed Mantle Cell Lymphoma (MCL) and Diffuse Large B-Cell Lymphoma (NCT NCT00294632)

Last Updated: 2020-02-24

Results Overview

MTD is defined as the highest dose level in which 1 or fewer participants experienced a dose limiting toxicity (DLT) in 6 participants treated. DLT is any grade III or IV toxicity during the first 28 days (first cycle) of therapy.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

54 participants

Primary outcome timeframe

28 days of cycle 1

Results posted on

2020-02-24

Participant Flow

Recruitment Period: February 7, 2006 to February 21, 2011. All recruitment done at The University of Texas MD Anderson Cancer Center.

There were 112 participants recruited for registration, 58 were screen failures prior to study inclusion

Participant milestones

Participant milestones
Measure	Phase I: Lenalidomide + Rituximab Lenalidomide Starting Dose 10 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks	Phase II: Lenalidomide 20 mg + Rituximab Lenalidomide MTD Dose 20 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks
Phase I Dose Escalation Period STARTED	14	0
Phase I Dose Escalation Period Cohort 1: 10 mg	3	0
Phase I Dose Escalation Period Cohort 2: 15 mg	3	0
Phase I Dose Escalation Period Cohort 3: 20 mg	6	0
Phase I Dose Escalation Period Cohort 4: 25 mg	2	0
Phase I Dose Escalation Period COMPLETED	14	0
Phase I Dose Escalation Period NOT COMPLETED	0	0
Phase II: 20 mg Lenalidomide STARTED	6	38
Phase II: 20 mg Lenalidomide COMPLETED	6	38
Phase II: 20 mg Lenalidomide NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Lenalidomide and Rituximab in the Treatment of Relapsed Mantle Cell Lymphoma (MCL) and Diffuse Large B-Cell Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1: Lenalidomide + Rituximab n=14 Participants Lenalidomide Starting Dose 10 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks	Phase II: Lenalidomide 20 mg + Rituximab n=38 Participants Lenalidomide MTD Dose 20 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks	Total n=52 Participants Total of all reporting groups
Age, Continuous	72 years n=5 Participants	64 years n=7 Participants	66 years n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	35 Participants n=7 Participants	47 Participants n=5 Participants
Region of Enrollment United States	14 participants n=5 Participants	38 participants n=7 Participants	52 participants n=5 Participants

PRIMARY outcome

Timeframe: 28 days of cycle 1

Outcome measures

Outcome measures
Measure	Phase I: Lenalidomide + Rituximab n=14 Participants Lenalidomide Starting Dose 10 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks
Maximum Tolerated Dose (MTD) of Lenalidomide in Combination With Rituximab	20 mg

SECONDARY outcome

Timeframe: 56 days, assessed after 2 cycles

Population: Total analyzed includes Phase 2 participants (38) which includes six participants (6) that continued from Phase 1 who were treated with 20 mg Lenalidomide.

Response definitions for measurable disease from the International Workshop Standardized Response Criteria for non-Hodgkin's Lymphoma: Complete Response (CR): Disappearance of all clinical evidence of active tumor for a minimum of four weeks. Partial Response (PR): =/\>50% decrease in sum of products of all measured lesions persisting for \>four weeks. No lesion may increase in size \& no new lesion may appear. Minor Response (MR): \>25% but less than 50% response. Stable Disease: Steady state or response less than minor \& no progression for at least 8 weeks. There may be no appearance of significant new lesions. Progressive Disease: Unequivocal increase in size of any measurable lesion or appearance of significant new.

Outcome measures

Outcome measures
Measure	Phase I: Lenalidomide + Rituximab n=44 Participants Lenalidomide Starting Dose 10 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks
Response of Participants Treated at Lenalidomide 20 mg Complete Response	16 Participants
Response of Participants Treated at Lenalidomide 20 mg Partial Response	9 Participants
Response of Participants Treated at Lenalidomide 20 mg Stable Disease	10 Participants
Response of Participants Treated at Lenalidomide 20 mg Progressive Disease	9 Participants

SECONDARY outcome

Timeframe: 56 days

Population: Total analyzed includes Phase 2 participants (38) which includes six participants (6) that continued from Phase 1 who were treated with 20 mg Lenalidomide.

Objective response rate defined as percentage of participants with complete or partial response after 2 cycles of therapy maintained for one month. Objective response monitored using Simon's optimal 2-stage design.

Outcome measures

Outcome measures
Measure	Phase I: Lenalidomide + Rituximab n=44 Participants Lenalidomide Starting Dose 10 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks
Objective Response Rate of Participants Treated With Lenalidomide 20 mg: Overall Response as % of Participants With Complete or Partial Response	57 percentage of participants

Adverse Events

Phase I: Lenalidomide + Rituximab

Serious events: 9 serious events

Other events: 14 other events

Deaths: 1 deaths

Phase II: Lenalidomide

Serious events: 24 serious events

Other events: 44 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Dr. Michael Wang, Professor, Lymphoma/Myeloma

The University of Texas (UT) MD Anderson Cancer Center

Phone: 713-792-2860

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Phase I: Lenalidomide + Rituximab n=14 participants at risk Lenalidomide Starting Dose 10 mg, 15 mg, 20 mg or 25 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks	Phase II: Lenalidomide n=44 participants at risk Lenalidomide MTD Dose 20 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks
Infections and infestations Non-neutropenic infections	7.1% 1/14 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	0.00% 0/44 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Blood and lymphatic system disorders Neutropenia	35.7% 5/14 • Number of events 5 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	29.5% 13/44 • Number of events 13 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Blood and lymphatic system disorders Lymphopenia	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	9.1% 4/44 • Number of events 4 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hyperuricemia	7.1% 1/14 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Vascular disorders Thrombosis or thromboembolism	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hypercalcaemia	7.1% 1/14 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	4.5% 2/44 • Number of events 2 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Skin and subcutaneous tissue disorders Cellulitis	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Nervous system disorders Cerebral edema	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Psychiatric disorders Altered mental Status	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Vascular disorders Deep Vein Thrombosis	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	4.5% 2/44 • Number of events 3 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Nervous system disorders Snyocope	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Musculoskeletal and connective tissue disorders Muscle weakness	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	4.5% 2/44 • Number of events 2 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Vascular disorders Thrombocytopenia	7.1% 1/14 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	9.1% 4/44 • Number of events 5 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	4.5% 2/44 • Number of events 2 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Cardiac disorders Chest Pain	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	4.5% 2/44 • Number of events 2 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Renal and urinary disorders Acute Renal Insufficiency	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Injury, poisoning and procedural complications Post Radiation Treatment Complication	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Respiratory, thoracic and mediastinal disorders Pneumonia	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	4.5% 2/44 • Number of events 2 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Disease Progression	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
General disorders Abdominal Pain	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hypophosphatemia	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	2.3% 1/44 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Investigations Leucopenia/leukocytopenia	7.1% 1/14 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	6.8% 3/44 • Number of events 3 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
General disorders Death	7.1% 1/14 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	0.00% 0/44 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.

Other adverse events
Measure	Phase I: Lenalidomide + Rituximab n=14 participants at risk Lenalidomide Starting Dose 10 mg, 15 mg, 20 mg or 25 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks	Phase II: Lenalidomide n=44 participants at risk Lenalidomide MTD Dose 20 mg oral daily on Days 1-21 + Rituximab 375 mg/m\^2 intravenous weekly for 4 weeks
Blood and lymphatic system disorders Anaemia	100.0% 14/14 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	86.4% 38/44 • Number of events 38 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Blood and lymphatic system disorders Neutropenia	100.0% 14/14 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	100.0% 44/44 • Number of events 71 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Blood and lymphatic system disorders Febrile neutropenia	21.4% 3/14 • Number of events 3 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	22.7% 10/44 • Number of events 10 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Blood and lymphatic system disorders Thrombocytopenia	100.0% 14/14 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	95.5% 42/44 • Number of events 42 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Blood and lymphatic system disorders Leucopenia	92.9% 13/14 • Number of events 13 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	100.0% 44/44 • Number of events 53 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Blood and lymphatic system disorders Lymphopenia	100.0% 14/14 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	100.0% 44/44 • Number of events 64 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Skin and subcutaneous tissue disorders Pruritus	92.9% 13/14 • Number of events 13 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	50.0% 22/44 • Number of events 22 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
General disorders Fatigue	100.0% 14/14 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	86.4% 38/44 • Number of events 58 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Musculoskeletal and connective tissue disorders Limb pain	35.7% 5/14 • Number of events 5 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	15.9% 7/44 • Number of events 7 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Nervous system disorders Ataxia	7.1% 1/14 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	4.5% 2/44 • Number of events 2 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Respiratory, thoracic and mediastinal disorders Cough	71.4% 10/14 • Number of events 10 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	43.2% 19/44 • Number of events 19 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Investigations Increased liver function	78.6% 11/14 • Number of events 11 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	40.9% 18/44 • Number of events 18 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Nervous system disorders Syncope	7.1% 1/14 • Number of events 1 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	0.00% 0/44 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
General disorders Non-neutropenic infections	100.0% 14/14 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	63.6% 28/44 • Number of events 28 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hyperglycaemia	100.0% 14/14 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	93.2% 41/44 • Number of events 41 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Musculoskeletal and connective tissue disorders Myalgia	42.9% 6/14 • Number of events 6 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	68.2% 30/44 • Number of events 30 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hyperuricaemia	50.0% 7/14 • Number of events 7 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	31.8% 14/44 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hypercalcaemia	14.3% 2/14 • Number of events 2 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	6.8% 3/44 • Number of events 3 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Gastrointestinal disorders Constipation	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	68.2% 30/44 • Number of events 30 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Nervous system disorders Neuropathy	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	75.0% 33/44 • Number of events 33 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Gastrointestinal disorders Nausea	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	45.5% 20/44 • Number of events 20 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Gastrointestinal disorders Vomiting	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	34.1% 15/44 • Number of events 15 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Nervous system disorders Memory impairment	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	29.5% 13/44 • Number of events 13 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Psychiatric disorders Mood alteration	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	27.3% 12/44 • Number of events 12 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Nervous system disorders Dizziness	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	40.9% 18/44 • Number of events 18 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Eye disorders Blurred vision	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	34.1% 15/44 • Number of events 15 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Gastrointestinal disorders Oral cavity pain	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	34.1% 15/44 • Number of events 15 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Gastrointestinal disorders Abdominal pain	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	25.0% 11/44 • Number of events 11 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	52.3% 23/44 • Number of events 23 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	13.6% 6/44 • Number of events 6 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Gastrointestinal disorders Diarrhoea	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	65.9% 29/44 • Number of events 29 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Skin and subcutaneous tissue disorders Rash	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	65.9% 29/44 • Number of events 29 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hypophosphataemia	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	18.2% 8/44 • Number of events 8 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	6.8% 3/44 • Number of events 3 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	31.8% 14/44 • Number of events 14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Hypomagnesaemia	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	34.1% 15/44 • Number of events 15 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Raised blood urea nitrogen (BUN)	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	22.7% 10/44 • Number of events 10 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Raised Beta-2-Microglobulin (B2M)	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	29.5% 13/44 • Number of events 13 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
Metabolism and nutrition disorders Raised Lactate dehydrogenase (LDH or LD)	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	29.5% 13/44 • Number of events 13 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.
General disorders Facial oedema	0.00% 0/14 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.	9.1% 4/44 • Number of events 4 • From date of randomization until the date of death from any cause or study completion, whichever came first, assessed up to 10 years Phase 1 included a total 14 participants in the MTD determination while Phase 2 included 38 additional participants, reflected in the Adverse Reporting are 6 participants from Phase I dosed at 20 mg MTD to total 44 participants in that portion of the study.