Trial Outcomes & Findings for Lenalidomide, Fludarabine & Cyclophosphamide in Advanced Chronic Lymphocytic Leukemia Not Responding to Therapy (NCT NCT00727415)

Results Overview

Maximum tolerated dose of lenalidomide given in combination with fludarabine.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

42 participants

Primary outcome timeframe

The MTD of Lenalinomide will be evaluated during the two courses given with the escalated dose of Lenalinomide defined by the respective dose level.

Results posted on

2019-01-22

Participant Flow

Participant milestones

Participant milestones
Measure	Phase I-II Lenalidomide The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Phase I STARTED	9
Phase I COMPLETED	7
Phase I NOT COMPLETED	2
Phase II STARTED	33
Phase II COMPLETED	33
Phase II NOT COMPLETED	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase I-II Lenalidomide The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Phase I Dose Limiting Toxicity	2

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase I-II Lenalidomide n=40 Participants The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Age, Continuous	66 years n=40 Participants
Sex: Female, Male Female	10 Participants n=40 Participants
Sex: Female, Male Male	30 Participants n=40 Participants
Region of Enrollment Italy	40 participants n=40 Participants

PRIMARY outcome

Timeframe: The MTD of Lenalinomide will be evaluated during the two courses given with the escalated dose of Lenalinomide defined by the respective dose level.

Maximum tolerated dose of lenalidomide given in combination with fludarabine.

Outcome measures

Outcome measures
Measure	Phase I-II Lenalidomide n=9 Participants The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Maximum Tolerated Dose of Lenalidomide (Phase I) Dose level 1 - 5 mg	6 number of patients without DLT
Maximum Tolerated Dose of Lenalidomide (Phase I) Dose level 2 - 10 mg	1 number of patients without DLT

PRIMARY outcome

Timeframe: After 6 months from study entry (end of treatment).

Population: 7 patients coming from the phase I + 33 patients enrolled from the phase II. The whole population of phase II part of the trial is composed of a total of 40 patients.

Response will be assessed by clinical examination, peripheral blood, bone marrow aspirate and biopsy, radiographic evaluation. Response will be evaluated at three different levels: clinical, cytometric and molecular.

Outcome measures

Outcome measures
Measure	Phase I-II Lenalidomide n=40 Participants The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Overall Complete Response (CR) Rate (Phase II)	22.5 percentage of patients in CR

SECONDARY outcome

Timeframe: After 6 months from study entry (end of treatment)

Response will be assessed by clinical examination, peripheral blood, bone marrow aspirate and biopsy, radiographic evaluation. Response will be evaluated at three different levels: clinical, cytometric and molecular.

Outcome measures

Outcome measures
Measure	Phase I-II Lenalidomide n=40 Participants The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Number of Patients Reaching Disease-free Survival (DSF) Overall	35.33 percentage of participants on DFS Interval 22.71 to 54.95

SECONDARY outcome

Timeframe: At 24 months from study entry (end of follow-up)

Population: Fourteen (35%) patients have died.

Data from all subjects who receive any study drug will be included in the safety analyses.

Outcome measures

Outcome measures
Measure	Phase I-II Lenalidomide n=40 Participants The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Toxicity as Assessed by NCI CTCAE v3.0	14 Participants who died during the study

SECONDARY outcome

Timeframe: At 24 months from study entry (end of follow-up)

Severe infection requiring more than 2 weeks of antibiotic therapy.

Outcome measures

Outcome measures
Measure	Phase I-II Lenalidomide n=40 Participants The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Number of Patients With Severe Infections	2 participants with severe infecitons

SECONDARY outcome

Timeframe: After 6 months from study entry (end of treatment).

Outcome measures

Outcome measures
Measure	Phase I-II Lenalidomide n=42 Participants The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). CR according to IgHV mutated	28.00 percentage of participants
Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). CR according to CD19+/CD38+, <30%	33.33 percentage of participants
Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). CR according to CD19+/CD38+, >30%	16.67 percentage of participants
Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). CR according to deletion 11q and 17p, absent	31.82 percentage of participants

Adverse Events

Phase I-II Lenalidomide

Serious events: 8 serious events

Other events: 0 other events

Deaths: 14 deaths

Serious adverse events

Serious adverse events
Measure	Phase I-II Lenalidomide n=40 participants at risk The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced. The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT. In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg.
Infections and infestations Bronchopneumonia	5.0% 2/40 • Number of events 2
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	2.5% 1/40 • Number of events 1
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.5% 1/40 • Number of events 1
General disorders Multi-organi failure	2.5% 1/40 • Number of events 1
Cardiac disorders Supraventricular tachycardia	2.5% 1/40 • Number of events 1
Blood and lymphatic system disorders Febrile neutropenia	5.0% 2/40 • Number of events 3
Injury, poisoning and procedural complications Craniocerebral injury	2.5% 1/40 • Number of events 1
Blood and lymphatic system disorders Pancytopenia	2.5% 1/40 • Number of events 1
Cardiac disorders Atrial fibrillation	2.5% 1/40 • Number of events 1
General disorders Intestinal obstruction	2.5% 1/40 • Number of events 1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) myelodisplastic syndrome	2.5% 1/40 • Number of events 1

Other adverse events

Adverse event data not reported

Additional Information

Alfonso Piciocchi

GIMEMA

Phone: +39 06 70390513

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place