Acute Lymphoblastic Leukemia, Acute Myelogenous Leukemia, Relapsed Leukemia
Conditions
Keywords
clofarabine, acute leukemia, ALL, AML, clolar, CLO218
Brief summary
Clofarabine (injection) is approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted. The purpose of the phase 1 portion of this study was to determine if clofarabine added to a combination of etoposide and cyclophosphamide is safe in children with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). The purpose of the phase 2 portion of the study was to measure the effectiveness of the combination therapy in children with ALL.
Interventions
DRUGclofarabine
Clofarabine 20-40 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle as the first of the three IV interventions administered. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
DRUGEtoposide
Etoposide 75-100 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle following clofarabine therapy. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
DRUGCyclophosphamide
Cyclophosphamide 340-440 mg/m²/day as 30-60 minute intravenous (IV) infusion daily for 5 days of a 28 day cycle following the other two interventions. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* NOTE: the following eligibility criteria were applicable to acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study). * ALL with \> 25% blasts in bone marrow; AML with ≥ 5% blasts in bone marrow; ALL and AML patients may have extramedullary disease * Karnofsky Performance Status ≥ 50 for patients \> 10 years old; Lansky Performance Status ≥ 50 for patients ≤ 10 years old * Prior therapy: AML: 1-2 prior induction regimens and ≤ 1 hematopoietic stem cell transplant (HSCT); ALL: 1-3 prior induction regimens * Adequate liver, renal, pancreatic, and cardiac function * Have received no prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)
Exclusion criteria
* NOTE: the following eligibility criteria were applicable to ALL and AML patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study). * Burkitt's leukemia * Previous treatment with clofarabine * Uncontrolled systemic fungal, bacterial or other infection and 48 hrs negative blood cultures required for patients with a history of fever within 3 days of enrollment * Active CNS involvement (i.e., should be CNS1 or CNS2) * Inadequate time since last therapy: ≤ 14 days since last cytotoxic chemotherapy; ≤ 7 days since last biologic therapy; ≤ 14 days since last monoclonal antibody therapy * Have received prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT) * Pregnant or lactating * Have tested positive for hepatitis B or hepatitis C infection or history of cirrhosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) in Phase 1 | Up to Day 42 (Phase 1 portion of study) | The MTD was to be the highest dose level of clofarabine in combination with etoposide and cyclophosphamide that caused \<= 1 of 6 participants to experience a dose limiting toxicity (DLT) with the next higher dose level having at least 2 of 3 or 2 of 6 participants experiencing a DLT. The MTD would be used as the recommended phase 2 dose (RP2D). If the MTD could not be determined, then the target dose of clofarabine 40 mg/m\^2, etoposide 100 mg/m\^2 and cyclophosphamide 440 mg/m\^2 as taken by Cohort 5 was to become the RP2D. The rating scale used is 0 = not the MTD, 1 = the MTD. |
| Participants With Dose Limiting Toxicity in Phase 1 | Up to Day 42 (Phase 1 portion of study) | The number of participants in each cohort that had dose limiting toxicity is summarized. Toxicities were reviewed by an independent Data Safety Monitoring Board (DSMB) who determined if additional participants should be added to the cohort and the criteria for escalating to the next cohort. |
| Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 | Approximately 28-56 days (Phase 2 portion of study) | Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with \<5% blasts, and platelet (plt)/ANC recovery: ≥75/ ≥0.75 \[x 10\^9/L\] 2) CR in absence of plt recovery (CRp): plt ≥20 to \<75 x 10\^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with \<5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1 | Up to 2 years (Phase 1 portion of study) | Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks. |
| Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1 | Up to 2 years (Phase 1 portion of study) | Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks. |
| Number of Participants With 4-month Event Free Survival in Phase 1 | 4 months (Phase I portion of study) | Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse. |
| Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1 | Up to 2 years (Phase 1 portion of study) | Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks. |
| Summary of Participants With Adverse Events (AEs) in Phase 2 | Up to 9.5 months (Phase 2 portion of study) | Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0) and relationship to study drug. The severity scale is:\> Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE |
| Summary of Participants With Adverse Events (AEs) in Phase 1 | Up to 9.5 months (Phase 1 portion of study) | Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0) and relationship to study drug. The severity scale is:\> Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE |
| Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2 | Up to 2 years (Phase 2 portion of study) | Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks. |
| Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2 | Up to 2 years (Phase 2 portion of study) | Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks. |
| Number of Participants With 4-month Event Free Survival in Phase 2 | 4 months (Phase 2 portion of study) | Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse. |
| Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2 | Up to 2 years (Phase 2 portion of study) | Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks. |
| Time to Remission for Participants Who Had a Response in Phase 2 | up to 8 weeks (Phase 2 portion of study) | The weeks between start of intervention and remission as assessed by the investigator in Phase 2. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included. |
| Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 | Approximately 2 months (Phase 1 portion of study) | Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with \<5% blasts, and platelet (plt)/ANC recovery: ALL ≥75/ ≥0.75 \[x 10\^9/L\]; AML ≥100/ ≥1.0 \[x 10\^9/L\] 2) CR in absence of plt recovery (CRp): ALL plt ≥20 to \<75 x 10\^9/L; AML plt ≥20 to \<100 x 10\^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with \<5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR. |
| Time to Remission for Participants Who Had a Response in Phase 1 | up to 8 weeks (Phase 1 portion of study) | The weeks between start of intervention and remission as assessed by the investigator in Phase 1. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Clofarabine, Etoposide, Cyclophosphamide Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m\^2, etoposide dosage from 75-100 mg/m\^2, cyclophosphamide dosage from 340-440 mg/m\^2. | 25 |
| Phase 2: Clofarabine, Etoposide, Cyclophosphamide Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m\^2, etoposide 100 mg/m\^2 and cyclophosphamide 440 mg/m\^2 delivered intravenously | 25 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Phase 1 | Death | 3 |
| Phase 1 | Disease relapse | 4 |
| Phase 1 | Failure to achieve response | 8 |
| Phase 1 | Refused further treatment | 1 |
| Phase 1 | Scheduled for transplant | 9 |
| Phase 2 | Adverse Event | 1 |
| Phase 2 | Death | 7 |
| Phase 2 | Disease relapse | 1 |
| Phase 2 | Failure to achieve response | 3 |
| Phase 2 | Other | 1 |
| Phase 2 | Physician Decision | 4 |
| Phase 2 | Scheduled for transplant | 8 |
Baseline characteristics
| Characteristic | Phase 1: Clofarabine, Etoposide, Cyclophosphamide | Total | Phase 2: Clofarabine, Etoposide, Cyclophosphamide |
|---|---|---|---|
| Absolute Neutrophil Counts | 1.93828 10^9/L STANDARD_DEVIATION 3.049992 | 1.93325 10^9/L STANDARD_DEVIATION 2.459536 | 1.9280 10^9/L STANDARD_DEVIATION 1.708126 |
| Age, Continuous | 9.1 years STANDARD_DEVIATION 5.03 | 11.2 years STANDARD_DEVIATION 5.49 | 13.2 years STANDARD_DEVIATION 5.25 |
| Count of Previous Anti-Leukemic (non-transplant) Treatment Regimens 1 regimen | 4 participants | 8 participants | 4 participants |
| Count of Previous Anti-Leukemic (non-transplant) Treatment Regimens 2 regimens | 18 participants | 32 participants | 14 participants |
| Count of Previous Anti-Leukemic (non-transplant) Treatment Regimens 3 regimens | 3 participants | 10 participants | 7 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 15 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 35 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Immunophenotype B cell | 13 participants | 34 participants | 21 participants |
| Immunophenotype not included (AML participants) | 5 participants | 5 participants | 0 participants |
| Immunophenotype T cell | 5 participants | 6 participants | 1 participants |
| Immunophenotype Unknown | 2 participants | 5 participants | 3 participants |
| Participant Rating Using the Karnofsky/Lansky Performance Status Scale 100 | 12 participants | 22 participants | 10 participants |
| Participant Rating Using the Karnofsky/Lansky Performance Status Scale 50 | 0 participants | 2 participants | 2 participants |
| Participant Rating Using the Karnofsky/Lansky Performance Status Scale 60 | 0 participants | 2 participants | 2 participants |
| Participant Rating Using the Karnofsky/Lansky Performance Status Scale 70 | 1 participants | 3 participants | 2 participants |
| Participant Rating Using the Karnofsky/Lansky Performance Status Scale 80 | 5 participants | 8 participants | 3 participants |
| Participant Rating Using the Karnofsky/Lansky Performance Status Scale 90 | 7 participants | 13 participants | 6 participants |
| Participants Who Were Refractory to the Most Recent Previous Anti-Leukemic Treatment No | 18 participants | 28 participants | 10 participants |
| Participants Who Were Refractory to the Most Recent Previous Anti-Leukemic Treatment Yes | 7 participants | 22 participants | 15 participants |
| Participants with Previous Anti-Leukemic Transplant Regimens No transplants | 21 participants | 42 participants | 21 participants |
| Participants with Previous Anti-Leukemic Transplant Regimens Transplants | 4 participants | 8 participants | 4 participants |
| Percent Leukemic Blast Cells | 66.8 percentage of total blast cells STANDARD_DEVIATION 24.85 | 68.16 percentage of total blast cells STANDARD_DEVIATION 24.008 | 69.52 percentage of total blast cells STANDARD_DEVIATION 23.566 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 10 Participants | 8 Participants |
| Race (NIH/OMB) White | 16 Participants | 28 Participants | 12 Participants |
| Sex: Female, Male Female | 10 Participants | 19 Participants | 9 Participants |
| Sex: Female, Male Male | 15 Participants | 31 Participants | 16 Participants |
| White Blood Cell Counts | 8.323 10^9/L STANDARD_DEVIATION 9.1305 | 10.247 10^9/L STANDARD_DEVIATION 17.437 | 12.171 10^9/L STANDARD_DEVIATION 23.015 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 10 / 10 | 6 / 6 | 25 / 25 | 25 / 25 |
| serious Total, serious adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 9 / 10 | 6 / 6 | 24 / 25 | 21 / 25 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) in Phase 1
The MTD was to be the highest dose level of clofarabine in combination with etoposide and cyclophosphamide that caused \<= 1 of 6 participants to experience a dose limiting toxicity (DLT) with the next higher dose level having at least 2 of 3 or 2 of 6 participants experiencing a DLT. The MTD would be used as the recommended phase 2 dose (RP2D). If the MTD could not be determined, then the target dose of clofarabine 40 mg/m\^2, etoposide 100 mg/m\^2 and cyclophosphamide 440 mg/m\^2 as taken by Cohort 5 was to become the RP2D. The rating scale used is 0 = not the MTD, 1 = the MTD.
Time frame: Up to Day 42 (Phase 1 portion of study)
Population: All phase 1 participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Cohort 1 | Maximum Tolerated Dose (MTD) in Phase 1 | 0 units on a scale |
| Phase 1 - Cohort 2 | Maximum Tolerated Dose (MTD) in Phase 1 | 0 units on a scale |
| Phase 1 - Cohort 3 | Maximum Tolerated Dose (MTD) in Phase 1 | 0 units on a scale |
| Phase 1 - Cohort 4 | Maximum Tolerated Dose (MTD) in Phase 1 | 0 units on a scale |
| Phase 1 - Cohort 5 | Maximum Tolerated Dose (MTD) in Phase 1 | 0 units on a scale |
Primary
Participants With Dose Limiting Toxicity in Phase 1
The number of participants in each cohort that had dose limiting toxicity is summarized. Toxicities were reviewed by an independent Data Safety Monitoring Board (DSMB) who determined if additional participants should be added to the cohort and the criteria for escalating to the next cohort.
Time frame: Up to Day 42 (Phase 1 portion of study)
Population: All phase 1 participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Cohort 1 | Participants With Dose Limiting Toxicity in Phase 1 | 0 participants |
| Phase 1 - Cohort 2 | Participants With Dose Limiting Toxicity in Phase 1 | 0 participants |
| Phase 1 - Cohort 3 | Participants With Dose Limiting Toxicity in Phase 1 | 0 participants |
| Phase 1 - Cohort 4 | Participants With Dose Limiting Toxicity in Phase 1 | 1 participants |
| Phase 1 - Cohort 5 | Participants With Dose Limiting Toxicity in Phase 1 | 1 participants |
Primary
Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2
Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with \<5% blasts, and platelet (plt)/ANC recovery: ≥75/ ≥0.75 \[x 10\^9/L\] 2) CR in absence of plt recovery (CRp): plt ≥20 to \<75 x 10\^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with \<5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.
Time frame: Approximately 28-56 days (Phase 2 portion of study)
Population: All phase 2 participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 | Complete remission (CR) | 28 percentage of total participants |
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 | Complete remission/absence total platelet recovery | 16 percentage of total participants |
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 | Partial remission (PR) | 12 percentage of total participants |
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 | Overall remission (OR) | 44 percentage of total participants |
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 | Any response (CR+CRp+PR) | 56 percentage of total participants |
Secondary
Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1
Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks.
Time frame: Up to 2 years (Phase 1 portion of study)
Population: Phase 1 participants who achieved overall remission. Data are censored at date of last known follow-up visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Cohort 1 | Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1 | 18.2 weeks |
Secondary
Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2
Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks.
Time frame: Up to 2 years (Phase 2 portion of study)
Population: Phase 2 participants who achieved overall remission. Data are censored at date of last known follow-up visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Cohort 1 | Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2 | 67.3 weeks |
Secondary
Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1
Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks.
Time frame: Up to 2 years (Phase 1 portion of study)
Population: All phase 1 participants. Data are censored at date of last known follow-up visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Cohort 1 | Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1 | 19.3 weeks |
Secondary
Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2
Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks.
Time frame: Up to 2 years (Phase 2 portion of study)
Population: All phase 2 participants. Data are censored at date of last known follow-up visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Cohort 1 | Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2 | 10.7 weeks |
Secondary
Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1
Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks.
Time frame: Up to 2 years (Phase 1 portion of study)
Population: All phase 1 participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Cohort 1 | Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1 | 27.1 weeks |
Secondary
Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2
Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks.
Time frame: Up to 2 years (Phase 2 portion of study)
Population: All phase 2 participants. Data are censored at date of last known follow-up visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - Cohort 1 | Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2 | 10.7 weeks |
Secondary
Number of Participants With 4-month Event Free Survival in Phase 1
Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse.
Time frame: 4 months (Phase I portion of study)
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Cohort 1 | Number of Participants With 4-month Event Free Survival in Phase 1 | 13 participants |
Secondary
Number of Participants With 4-month Event Free Survival in Phase 2
Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse.
Time frame: 4 months (Phase 2 portion of study)
Population: All participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Cohort 1 | Number of Participants With 4-month Event Free Survival in Phase 2 | 11 participants |
Secondary
Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1
Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with \<5% blasts, and platelet (plt)/ANC recovery: ALL ≥75/ ≥0.75 \[x 10\^9/L\]; AML ≥100/ ≥1.0 \[x 10\^9/L\] 2) CR in absence of plt recovery (CRp): ALL plt ≥20 to \<75 x 10\^9/L; AML plt ≥20 to \<100 x 10\^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with \<5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.
Time frame: Approximately 2 months (Phase 1 portion of study)
Population: All phase 1 participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 | Complete remission (CR) | 40 percentage of total participants |
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 | Complete remission/absence total platelet recovery | 24 percentage of total participants |
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 | Partial remission (PR) | 0 percentage of total participants |
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 | Overall remission (OR) | 64 percentage of total participants |
| Phase 1 - Cohort 1 | Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 | Any response (CR+CRp+PR) | 64 percentage of total participants |
Secondary
Summary of Participants With Adverse Events (AEs) in Phase 1
Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0) and relationship to study drug. The severity scale is:\> Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE
Time frame: Up to 9.5 months (Phase 1 portion of study)
Population: All phase 1 participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Discontinued study due to AE | 0 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 1 | 0 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Died | 3 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE related to clofarabine | 3 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 5 | 0 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 4 | 1 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE | 3 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE | 3 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 3 | 2 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE related to clofarabine | 3 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 2 | 0 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE related to clofarabine | 2 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 5 | 1 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 1 | 0 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE | 3 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE | 3 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Died | 1 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 4 | 1 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 3 | 1 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE related to clofarabine | 3 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 2 | 0 participants |
| Phase 1 - Cohort 2 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Discontinued study due to AE | 0 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 4 | 2 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE | 3 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE related to clofarabine | 3 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE | 3 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE related to clofarabine | 3 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Discontinued study due to AE | 0 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Died | 3 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 1 | 0 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 2 | 0 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 3 | 1 participants |
| Phase 1 - Cohort 3 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 5 | 0 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Discontinued study due to AE | 0 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 1 | 0 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE related to clofarabine | 9 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE related to clofarabine | 10 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 2 | 0 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE | 9 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 3 | 3 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE | 10 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 4 | 5 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Died | 9 participants |
| Phase 1 - Cohort 4 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 5 | 2 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 4 | 2 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 3 | 3 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 1 | 0 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE related to clofarabine | 5 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE related to clofarabine | 6 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Discontinued study due to AE | 0 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one AE | 6 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 2 | 0 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | At least one serious AE | 6 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | Died | 5 participants |
| Phase 1 - Cohort 5 | Summary of Participants With Adverse Events (AEs) in Phase 1 | AE with the worst grade of: 5 | 1 participants |
Secondary
Summary of Participants With Adverse Events (AEs) in Phase 2
Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0) and relationship to study drug. The severity scale is:\> Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE
Time frame: Up to 9.5 months (Phase 2 portion of study)
Population: All phase 2 participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | At least one AE | 25 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | At least one AE related to clofarabine | 25 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | At least one serious AE | 21 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | At least one serious AE related to clofarabine | 20 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | Discontinued study due to AE | 1 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | Died | 16 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | AE with the worst grade of: 1 | 0 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | AE with the worst grade of: 2 | 0 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | AE with the worst grade of: 3 | 1 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | AE with the worst grade of: 4 | 16 participants |
| Phase 1 - Cohort 1 | Summary of Participants With Adverse Events (AEs) in Phase 2 | AE with the worst grade of: 5 | 8 participants |
Secondary
Time to Remission for Participants Who Had a Response in Phase 1
The weeks between start of intervention and remission as assessed by the investigator in Phase 1. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included.
Time frame: up to 8 weeks (Phase 1 portion of study)
Population: Participants in phase 1 who had an overall remission.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 - Cohort 1 | Time to Remission for Participants Who Had a Response in Phase 1 | 4.96 weeks | Standard Deviation 1.912 |
Secondary
Time to Remission for Participants Who Had a Response in Phase 2
The weeks between start of intervention and remission as assessed by the investigator in Phase 2. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included.
Time frame: up to 8 weeks (Phase 2 portion of study)
Population: Participants in phase 2 who had an overall remission.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 - Cohort 1 | Time to Remission for Participants Who Had a Response in Phase 2 | 4.84 weeks | Standard Deviation 2.092 |