Trial Outcomes & Findings for RAD001 Study in Treatment of Relapsed or Refractory Acute Lymphocytic Leukemia (NCT NCT00968253)

Last Updated: 2019-02-27

Results Overview

The Maximum tolerated dose (MTD) was the highest dose level at which fewer than 2 of 6 patients developed a dose limiting toxicity (DLT) in the first two cycles of therapy. A 3 by 3 design was used for dose escalation in the phase I portion of the study. A dose-limiting toxic effect (DLT) was defined as a clinically significant adverse event or abnormal laboratory value directly attributable to everolimus and assessed as unrelated to disease progression, intercurrent illness, or concomitant medications, occurring during the first or second cycle of therapy, that met any of the following criteria: CTCAE version 3.0 grade 3 increased AST or ALT for 7 days, CTCAE grade 4 increased AST or ALT of any duration, or any other clinically significant CTCAE grade 3 or 4 toxic effect. Electrolyte abnormalities (changes in glucose, chemistries, liver enzymes, pancreatic enzymes) correctable by optimal therapy and without clinical impact were not considered DLTs.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

24 participants

Primary outcome timeframe

Following first two dose cycles (21 days/each), up to 42 days

Results posted on

2019-02-27

Participant Flow

Recruitment Period: November 18, 2009 to March 21, 2014. All recruitment done at The University of Texas MD Anderson Cancer Center.

Participant milestones

Participant milestones
Measure	Phase I: RAD001 5 mg + Combination Chemo Everolimus (RAD001) beginning oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Cytarabine (Ara-C) during Even Cycles. First chemo combo Hyper-CVAD = Cyclophosphamide 300 mg/m\^2 intravenous (IV) every 12 hours x 6 doses on Days 1-3 (total dose 1800 mg/m2), Vincristine 2 mg IV on Day 4 \& Day 11, Adriamycin (doxorubicin) 50 mg/m\^2 IV over 24 hours Day 4, after last dose Cyclophosphamide, and Dexamethasone daily 40 mg IV or orally Days 1-4 \& Days 11-14 with second Methotrexate 200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours Day 1 \& Ara-C 3 gm/m\^2 IV every 12 hours for 4 doses Days 2, 3. Days 1-3, Mesna: 600 mg/m\^2 IV continuous infusion daily and Methylprednisone: 50 mg IV every 12 hours for 6 doses. G-CSF: 10 mcg/kg/day within 72 after completion of chemo until neutrophil recovery 1 x 10\^9/L or higher.	Phase I: RAD001 10 mg + Combination Chemo RAD001 oral dose 10 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Cytarabine (Ara-C) during Even Cycles. First chemo combo Hyper-CVAD = Cyclophosphamide 300 mg/m\^2 intravenous (IV) every 12 hours x 6 doses on Days 1-3 (total dose 1800 mg/m2), Vincristine 2 mg IV on Day 4 \& Day 11, Adriamycin (doxorubicin) 50 mg/m\^2 IV over 24 hours Day 4, after last dose Cyclophosphamide, and Dexamethasone daily 40 mg IV or orally Days 1-4 \& Days 11-14 with second Methotrexate 200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours Day 1 \& Ara-C 3 gm/m\^2 IV every 12 hours for 4 doses Days 2, 3. Days 1-3, Mesna: 600 mg/m\^2 IV continuous infusion daily and Methylprednisone: 50 mg IV every 12 hours for 6 doses. G-CSF: 10 mcg/kg/day within 72 after completion of chemo until neutrophil recovery 1 x 10\^9/L or higher.	Phase II: MTD RAD001 + Combination Chemo RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Cytarabine (Ara-C) during Even Cycles. First chemo combo Hyper-CVAD = Cyclophosphamide 300 mg/m\^2 intravenous (IV) every 12 hours x 6 doses on Days 1-3 (total dose 1800 mg/m2), Vincristine 2 mg IV on Day 4 \& Day 11, Adriamycin (doxorubicin) 50 mg/m\^2 IV over 24 hours Day 4, after last dose Cyclophosphamide, and Dexamethasone daily 40 mg IV or orally Days 1-4 \& Days 11-14 with second Methotrexate 200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours Day 1 \& Ara-C 3 gm/m\^2 IV every 12 hours for 4 doses Days 2, 3. Days 1-3, Mesna: 600 mg/m\^2 IV continuous infusion daily and Methylprednisone: 50 mg IV every 12 hours for 6 doses. G-CSF: 10 mcg/kg/day within 72 after completion of chemo until neutrophil recovery 1 x 10\^9/L or higher.
Overall Study STARTED	3	9	12
Overall Study COMPLETED	3	6	5
Overall Study NOT COMPLETED	0	3	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I: RAD001 10 mg + Combination Chemo RAD001 oral dose 10 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Cytarabine (Ara-C) during Even Cycles. First chemo combo Hyper-CVAD = Cyclophosphamide 300 mg/m\^2 intravenous (IV) every 12 hours x 6 doses on Days 1-3 (total dose 1800 mg/m2), Vincristine 2 mg IV on Day 4 \& Day 11, Adriamycin (doxorubicin) 50 mg/m\^2 IV over 24 hours Day 4, after last dose Cyclophosphamide, and Dexamethasone daily 40 mg IV or orally Days 1-4 \& Days 11-14 with second Methotrexate 200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours Day 1 \& Ara-C 3 gm/m\^2 IV every 12 hours for 4 doses Days 2, 3. Days 1-3, Mesna: 600 mg/m\^2 IV continuous infusion daily and Methylprednisone: 50 mg IV every 12 hours for 6 doses. G-CSF: 10 mcg/kg/day within 72 after completion of chemo until neutrophil recovery 1 x 10\^9/L or higher.	Phase II: MTD RAD001 + Combination Chemo RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Cytarabine (Ara-C) during Even Cycles. First chemo combo Hyper-CVAD = Cyclophosphamide 300 mg/m\^2 intravenous (IV) every 12 hours x 6 doses on Days 1-3 (total dose 1800 mg/m2), Vincristine 2 mg IV on Day 4 \& Day 11, Adriamycin (doxorubicin) 50 mg/m\^2 IV over 24 hours Day 4, after last dose Cyclophosphamide, and Dexamethasone daily 40 mg IV or orally Days 1-4 \& Days 11-14 with second Methotrexate 200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours Day 1 \& Ara-C 3 gm/m\^2 IV every 12 hours for 4 doses Days 2, 3. Days 1-3, Mesna: 600 mg/m\^2 IV continuous infusion daily and Methylprednisone: 50 mg IV every 12 hours for 6 doses. G-CSF: 10 mcg/kg/day within 72 after completion of chemo until neutrophil recovery 1 x 10\^9/L or higher.
Overall Study Death	0	2
Overall Study Withdrawal by Subject	0	1
Overall Study Disease Progression	3	3
Overall Study Adverse Event	0	1

Baseline Characteristics

RAD001 Study in Treatment of Relapsed or Refractory Acute Lymphocytic Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I: RAD001 5 mg + Combination Chemo n=3 Participants RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase I: RAD001 10 mg + Combination Chemo n=9 Participants RAD001 oral dose 10 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase II: MTD RAD001 + Combination Chemo n=12 Participants RAD001 MTD oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Total n=24 Participants Total of all reporting groups
Age, Continuous	29 years n=5 Participants	24 years n=7 Participants	30 years n=5 Participants	25 years n=4 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants	17 Participants n=4 Participants
Region of Enrollment United States	3 participants n=5 Participants	9 participants n=7 Participants	12 participants n=5 Participants	24 participants n=4 Participants

PRIMARY outcome

Timeframe: Following first two dose cycles (21 days/each), up to 42 days

Population: Maximum tolerated dose was an outcome measure for the phase I portion of this study only. MTD was already established, therefore, not analyzed on the participants for the phase II portion of this study.

Outcome measures

Outcome measures
Measure	Phase I: RAD001 5 mg + Combination Chemo n=3 Participants RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase I: RAD001 10 mg + Combination Chemo n=6 Participants RAD001 oral dose 10 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase II: MTD RAD001 + Combination Chemo RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Cytarabine (Ara-C) during Even Cycles. First chemo combo Hyper-CVAD = Cyclophosphamide 300 mg/m\^2 intravenous (IV) every 12 hours x 6 doses on Days 1-3 (total dose 1800 mg/m2), Vincristine 2 mg IV on Day 4 \& Day 11, Adriamycin (doxorubicin) 50 mg/m\^2 IV over 24 hours Day 4, after last dose Cyclophosphamide, and Dexamethasone daily 40 mg IV or orally Days 1-4 \& Days 11-14 with second Methotrexate 200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours Day 1 \& Ara-C 3 gm/m\^2 IV every 12 hours for 4 doses Days 2, 3. Days 1-3, Mesna: 600 mg/m\^2 IV continuous infusion daily and Methylprednisone: 50 mg IV every 12 hours for 6 doses. G-CSF: 10 mcg/kg/day within 72 after completion of chemo until neutrophil recovery 1 x 10\^9/L or higher.
Maximum Tolerated Dose [MTD] Determination by Number of Participants With Dose Limiting Toxicity (DLT)	0 Participants	1 Participants	—

PRIMARY outcome

Timeframe: 8 courses of treatment, up to 24 weeks

Number of participants out of total treated who experienced a complete response response according to RECIST criteria either (CR + CRp) CR Without Platelet Recovery. Response (CR + CRp) defined as Complete remission (CR): Disappearance of all clinical and/or radiologic evidence of disease. Neutrophil count \> 1.0 x10\^9/L, platelet count \> 100 x10\^9/L, and blasts \< 5% in a normocellular or hypercellular marrow. Complete remission without platelet recovery (CRp): Peripheral blood and marrow parameters as for CR, but with platelet count \> 20 x 10\^9/L and \< 100 x 10\^9/L in the absence of platelet transfusions. CR with incomplete blood count recovery (CRi): Same as CR but platelets ≤ 100,000/mcl and/or neutrophils ≤ 1,000/mcl.

Outcome measures

Outcome measures
Measure	Phase I: RAD001 5 mg + Combination Chemo n=3 Participants RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase I: RAD001 10 mg + Combination Chemo n=9 Participants RAD001 oral dose 10 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase II: MTD RAD001 + Combination Chemo n=12 Participants RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Cytarabine (Ara-C) during Even Cycles. First chemo combo Hyper-CVAD = Cyclophosphamide 300 mg/m\^2 intravenous (IV) every 12 hours x 6 doses on Days 1-3 (total dose 1800 mg/m2), Vincristine 2 mg IV on Day 4 \& Day 11, Adriamycin (doxorubicin) 50 mg/m\^2 IV over 24 hours Day 4, after last dose Cyclophosphamide, and Dexamethasone daily 40 mg IV or orally Days 1-4 \& Days 11-14 with second Methotrexate 200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours Day 1 \& Ara-C 3 gm/m\^2 IV every 12 hours for 4 doses Days 2, 3. Days 1-3, Mesna: 600 mg/m\^2 IV continuous infusion daily and Methylprednisone: 50 mg IV every 12 hours for 6 doses. G-CSF: 10 mcg/kg/day within 72 after completion of chemo until neutrophil recovery 1 x 10\^9/L or higher.
Overall Response Rate (OR) Where OR = CR + CRp + CRi	33 percentage of participants	33 percentage of participants	33 percentage of participants

SECONDARY outcome

Timeframe: Up to 20 cycles of study drugs (21 day cycles) or till disease progression

Response defined as Complete remission (CR): Disappearance of all clinical and/or radiologic evidence of disease. Neutrophil count \> 1.0 x10\^9/L, platelet count \> 100 x10\^9/L, and blasts \< 5% in a normocellular or hypercellular marrow. Complete remission without platelet recovery (CRp): Peripheral blood and marrow parameters as for CR, but with platelet count \> 20 x 10\^9/L and \< 100 x 10\^9/L in the absence of platelet transfusions. CR with incomplete blood count recovery (CRi): Same as CR but platelets ≤ 100,000/mcl and/or neutrophils ≤ 1,000/mcl. Partial remission (PR): Peripheral blood count recovery as for CR, with decrease in marrow blasts by \> 50% from pretreatment values with no more than 25% leukemia/lymphoma cells in the marrow. Nonresponder, Other: All other responses will be considered failures.

Outcome measures

Outcome measures
Measure	Phase I: RAD001 5 mg + Combination Chemo n=3 Participants RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase I: RAD001 10 mg + Combination Chemo n=9 Participants RAD001 oral dose 10 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase II: MTD RAD001 + Combination Chemo n=12 Participants RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Cytarabine (Ara-C) during Even Cycles. First chemo combo Hyper-CVAD = Cyclophosphamide 300 mg/m\^2 intravenous (IV) every 12 hours x 6 doses on Days 1-3 (total dose 1800 mg/m2), Vincristine 2 mg IV on Day 4 \& Day 11, Adriamycin (doxorubicin) 50 mg/m\^2 IV over 24 hours Day 4, after last dose Cyclophosphamide, and Dexamethasone daily 40 mg IV or orally Days 1-4 \& Days 11-14 with second Methotrexate 200 mg/m\^2 IV over 2 hours followed by 800 mg/m\^2 IV over 22 hours Day 1 \& Ara-C 3 gm/m\^2 IV every 12 hours for 4 doses Days 2, 3. Days 1-3, Mesna: 600 mg/m\^2 IV continuous infusion daily and Methylprednisone: 50 mg IV every 12 hours for 6 doses. G-CSF: 10 mcg/kg/day within 72 after completion of chemo until neutrophil recovery 1 x 10\^9/L or higher.
Participant Responses by Daily Dose Level Assignment (RAD001 5 mg, 10 mg and MTD 5 mg) Complete Remission	1 participants	2 participants	3 participants
Participant Responses by Daily Dose Level Assignment (RAD001 5 mg, 10 mg and MTD 5 mg) Complete Remission without platelet recovery	0 participants	0 participants	1 participants
Participant Responses by Daily Dose Level Assignment (RAD001 5 mg, 10 mg and MTD 5 mg) CR with incomplete blood count recovery	0 participants	1 participants	0 participants
Participant Responses by Daily Dose Level Assignment (RAD001 5 mg, 10 mg and MTD 5 mg) Partial Remission	1 participants	1 participants	0 participants
Participant Responses by Daily Dose Level Assignment (RAD001 5 mg, 10 mg and MTD 5 mg) Nonresponder	1 participants	5 participants	8 participants

Adverse Events

Phase I: RAD001 5 mg + Combination Chemo

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Phase I: RAD001 10 mg + Combination Chemo

Serious events: 7 serious events

Other events: 9 other events

Deaths: 0 deaths

Phase II: MTD RAD001 + Combination Chemo

Serious events: 11 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Marina Konopleva, MD, PHD/Professor, Leukemia

The University of Texas (UT) MD Anderson Cancer Center

Phone: 713-792-7734

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Phase I: RAD001 5 mg + Combination Chemo n=3 participants at risk RAD001 oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase I: RAD001 10 mg + Combination Chemo n=9 participants at risk RAD001 oral dose 10 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.	Phase II: MTD RAD001 + Combination Chemo n=12 participants at risk RAD001 MTD oral dose 5 mg every other day before chemo + two different chemotherapy combinations during alternating cycles, Hyper-CVAD on Odd Cycles and Methotrexate \& Ara-C during Even Cycles.
Blood and lymphatic system disorders Febrile Neutropenia	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	55.6% 5/9 • Number of events 5 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Blood and lymphatic system disorders Neutropenic Fever	33.3% 1/3 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	41.7% 5/12 • Number of events 10 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Cardiac disorders Chest Pain	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Infections and infestations Septic Shock	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	16.7% 2/12 • Number of events 2 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Infections and infestations Infection - E Coli Bacterium	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	11.1% 1/9 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
General disorders Multi-Organ Failure	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Respiratory, thoracic and mediastinal disorders Pleural effusions	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
General disorders Death	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	22.2% 2/9 • Number of events 2 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	25.0% 3/12 • Number of events 3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Renal and urinary disorders Cystitis	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	11.1% 1/9 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/12 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Gastrointestinal disorders Mucositis/Stomatitis	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	44.4% 4/9 • Number of events 5 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Cardiac disorders Sinus Tachycardia	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	11.1% 1/9 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/12 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Infections and infestations Pneumonia	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	33.3% 3/9 • Number of events 3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	16.7% 2/12 • Number of events 2 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Blood and lymphatic system disorders Pancytopenia	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Blood and lymphatic system disorders Hyponatremia	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Metabolism and nutrition disorders Alanine aminotransferase increased	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.
Metabolism and nutrition disorders Aspartate aminotransferase increased	0.00% 0/3 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	0.00% 0/9 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.	8.3% 1/12 • Number of events 1 • Adverse event collection for 8 courses of trial (21 day course), up to 24 weeks; SAEs reported from time consent is signed, during the course of treatment and within 30 days after the last day of active treatment.