Acute Lymphoblastic Leukemia (ALL)
Conditions
Keywords
acute, lymphoblastic, lymphocytic, leukemia, leukaemia, lukemia, leukimia, ALL, Marqibo, Hana Biosciences, vincristine, liposomal, liposome, optisome, hematology, malignancy, hematological, relapsed, anti-leukemia, adult, chemotherapy
Brief summary
This was a Phase 2, international, multicenter, open-label, single-arm trial evaluating Marqibo (VSLI) in adult subjects with: 1) Ph- ALL or lymphoblastic lymphoma in second or greater relapse; or 2) Ph- ALL or lymphoblastic lymphoma who failed 2 or greater treatment lines of anti-leukemia chemotherapy. The original enrollment target for this study was approximately 56 subjects. Per a protocol amendment, enrollment was increased from 56 to 65. The primary objective of this study was to evaluate: \- The efficacy of the study treatment as determined by the rate of CR plus CR with incomplete blood count recovery (CRi) in adult subjects with Philadelphia chromosome-negative (Ph-) ALL in second relapse or adult subjects with (Ph-) ALL who failed 2 treatment lines of anti-leukemia chemotherapy. Subjects must have achieved a CR to at least 1 prior anti-leukemia therapy as defined by a leukemia-free interval of ≥ 90 days.
Detailed description
The secondary objectives of this study were to evaluate: * Duration of CR plus CRi * Overall survival * Safety and tolerability
Interventions
Dosing was done every 7 days (± 3 days) on Days 1, 8, 15, and 22 with no less than 4 days between dosing days. Dose calculations were based on body surface area using the subject's height (from Screening) and actual weight for each course.
Sponsors
Parexel
Spectrum Pharmaceuticals, Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years. * Had Ph- ALL or lymphoblastic lymphoma and was in second relapse, or had failed 2 treatment lines of anti-leukemia chemotherapy. * Had histologically or cytologically proven ALL and ≥ 10% bone marrow blasts. If \< 10% bone marrow blasts, subject must have had histologically or cytologically proven ALL and evaluable extramedullary disease. Sponsor approval was obtained prior to enrolling subjects who had \< 10% bone marrow blasts with evaluable extramedullary disease. * Had achieved a CR to at least 1 prior anti-leukemia therapy as defined by a leukemia-free interval of ≥ 90 days. * For subjects with a prior history of stem cell transplantation, had ≤ Grade 1 active skin graft-versus-host disease (GVHD). No active gastrointestinal or liver graft-versus-host disease. * Had an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3. * Had normal renal and liver function as defined below within 14 days, inclusive, prior to first dose of VSLI, unless the abnormality was considered attributable to leukemia: * Total bilirubin ≤ 2.0 × institutional upper limit of normal, unless the subject had a known diagnosis of Gilbert's disease. If a subject had Gilbert's disease, he/she could have participated in this study, however must have been monitored closely during the study. * Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal. * Serum creatinine ≤ 2.0 g/dL or calculated estimated creatinine clearance ≥ 50 mL/minute/1.73 m2 based on Cockcroft and Gault formula, unless renal dysfunction was considered due to hematologic malignancy. * Had never received prior VSLI treatment. * For women of childbearing potential, had a negative serum or urine pregnancy test within 14 days prior to enrollment. * If female, the subject was postmenopausal, surgically sterilized, or willing to use acceptable methods of birth control (e.g., hormonal contraceptive, intra-uterine device, diaphragm with spermicide, and condom with spermicide or abstinence) from the Screening visit through 30 days after the last dose of VSLI. * If male, the subject agreed to use an acceptable barrier method for contraception from the Screening visit through 30 days after the last dose of VSLI. * Before enrollment, the subject was capable of understanding and complying with parameters as outlined in the protocol and able to sign a written informed consent according to ICH/GCP and national/local regulations.
Exclusion criteria
* Had Burkitt's lymphoma or Burkitt's leukemia. * Had a history of Philadelphia chromosome-positive (Ph+) ALL and/or BCR/ABL rearrangements documented by fluorescent in situ hybridization or polymerase chain reaction. * Had a history of Philadelphia chromosome-positive (Ph+) ALL and/or BCR/ABL rearrangements documented by fluorescent in situ hybridization or polymerase chain reaction. * Had active CNS disease. History of treated CNS disease was allowable. The CNS disease must have resolved in order for the subject to be eligible. * Was eligible for stem cell transplantation. This implied that a suitable donor was readily available, the subject was willing to undergo stem cell transplantation, and the Investigator believed this was a better treatment option than VSLI. This was at the Investigator's discretion. * Was treated with any investigational agents or chemotherapy agents in the last 21 days before the first dose of VSLI, unless full recovery from side effects had occurred or the subject had rapidly progressing disease judged to be life threatening by the Investigator. * Was receiving any other standard or investigational treatment for the subject's leukemia. * Intrathecal chemotherapy for CNS prophylaxis was allowable. * The use of hydroxyurea (Hydrea®) to control leukocytosis was allowable but must have been tapered off by Day 14 of Course 1. From Day 15 of Course 1 on through the end of study participation, hydroxyurea (Hydrea®) was not allowed. * Systemic corticosteroids must have been tapered off, preferably before the start of study treatment, but no later than by Day 5 of Course 1. From Day 6 of Course 1 on through the end of study participation, systemic corticosteroids were not allowed. * Had persistent chronic clinically significant toxicities from prior chemotherapy ≥ Grade 2 (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0). * Had persistent ≥ Grade 2 active neuropathy (NCI CTCAE v3.0). * Had a history of persistent ≥ Grade 2 active neurologic disorders unrelated to chemotherapy (including demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, or other demyelinating condition). * Had a history of allergic reactions or sensitivity attributed to compounds of similar chemical or biologic composition to vincristine or components of study drug. * Was female who was pregnant or breast-feeding. * Had active serious infection not controlled by oral or intravenous antibiotics or antifungals. * Had human immunodeficiency virus positive status. * Had any medical condition which in the opinion of the investigator placed the subject at an unacceptably high risk for toxicities. * Had any condition or circumstance which in the opinion of the investigator would significantly interfere with the subject's protocol compliance and put the subject at increased risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Plus Complete Remission Without Full Platelet Recovery (CR + CRi) | Response assessment performed at the end of each 28 day course. | CR is defined as no evidence of ALL: ANC\>or=1x10\^9/L or platelet count\>100x10\^9/L, absence of leukemia blast cells in blood and marrow (\<5% blasts), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery (CRi): As per CR but platelet count\< 100x10\^9/L or ANC\< 1x10\^9/L. Partial remission(PR):CR with\>5-25% abnormal cells in the marrow or 50% decrease in bone marrow blasts. Reduction in EMD by at least 50%. Hematologic Improvement. Bone marrow blast(BMB) response: BMB\<5% in the absence of HI. Stable disease(SD):No significant hematological and extramedullary change from baseline. |
| Clinical Response Assessment Per Independent Response Review Committee (IRRC) Evaluation | Response assessment at the end of each 28 days course | Number of subjects who achieved Complete Remission (CR)as assessed by the IRRC. CR is defined as no evidence of ALL. ANC\>=1X10\^9/L or Platelet count\>=100x10\^9/L, absence of blasts in blood and morrow (\<5%), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery(CRi)is defined as per CR but platelet count \<100x10\^9/L or ANC\<1x10\^9/L. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of CR + CRi | CR + CRi duration was calculated from the date the subject first met the definition of CR or CRi until the date of relapse | Duration of response for those subjects who achieved CR or CRi |
| Overall Survival | unlimited | Time, in days, from informed consent date until the date of death or date of last contact |
Countries
Canada, Germany, Israel, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled and treated at 22 sites in United States, Canada, Germany, Israel and United Kingdom. The first subject was infused on August 2, 2007. The last subject completed study on August 8, 2010.
Pre-assignment details
2.25 mg/m\^2 Marqibo administered intravenously via peripheral or central venous access over 60 minutes (+-10 minutes)
Participants by arm
| Arm | Count |
|---|---|
| Marqibo Eligible subjects received study drug at 2.25 mg/m2 intravenously via peripheral or central venous access over 60 minutes (± 10 minutes). | 65 |
| Total | 65 |
Baseline characteristics
| Characteristic | Marqibo |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 59 Participants |
| Age, Continuous | 36.3 years STANDARD_DEVIATION 16.37 |
| Region of Enrollment Canada | 2 participants |
| Region of Enrollment Germany | 4 participants |
| Region of Enrollment Israel | 6 participants |
| Region of Enrollment United States | 53 participants |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 65 / 65 |
| serious Total, serious adverse events | 21 / 65 |
Outcome results
Primary
Clinical Response Assessment Per Independent Response Review Committee (IRRC) Evaluation
Number of subjects who achieved Complete Remission (CR)as assessed by the IRRC. CR is defined as no evidence of ALL. ANC\>=1X10\^9/L or Platelet count\>=100x10\^9/L, absence of blasts in blood and morrow (\<5%), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery(CRi)is defined as per CR but platelet count \<100x10\^9/L or ANC\<1x10\^9/L.
Time frame: Response assessment at the end of each 28 days course
Population: The IRRC evaluable population included all subjects who received at least 1 dose of study drug and who has reviewable data to assess and determine response or lack of response as determined by the IRRC.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Marqibo | Clinical Response Assessment Per Independent Response Review Committee (IRRC) Evaluation | 11 participants |
Primary
Complete Remission Plus Complete Remission Without Full Platelet Recovery (CR + CRi)
CR is defined as no evidence of ALL: ANC\>or=1x10\^9/L or platelet count\>100x10\^9/L, absence of leukemia blast cells in blood and marrow (\<5% blasts), resolution of all sites of extramedullary disease (EMD). CR with incomplete blood count recovery (CRi): As per CR but platelet count\< 100x10\^9/L or ANC\< 1x10\^9/L. Partial remission(PR):CR with\>5-25% abnormal cells in the marrow or 50% decrease in bone marrow blasts. Reduction in EMD by at least 50%. Hematologic Improvement. Bone marrow blast(BMB) response: BMB\<5% in the absence of HI. Stable disease(SD):No significant hematological and extramedullary change from baseline.
Time frame: Response assessment performed at the end of each 28 day course.
Population: Subjects who had CR plus CRi by the PI and the IRRC assessments using the International Working Group Criteria. The Intent-to-Treat Analysis, n=65, minimum 1 dose. The IRRC, n=53, 1 dose, assess response as determined by the IRRC. Analyses, a Simon's 2-stage minimax design where the type I error alpha was set at 0.10 and the power was 80%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Marqibo | Complete Remission Plus Complete Remission Without Full Platelet Recovery (CR + CRi) | 13 participants |
Secondary
Duration of CR + CRi
Duration of response for those subjects who achieved CR or CRi
Time frame: CR + CRi duration was calculated from the date the subject first met the definition of CR or CRi until the date of relapse
Population: Based on the first date of CR or CRi to the date of the last available histologic assessment of the same response (n=8)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Marqibo | Duration of CR + CRi | 28 days |
Secondary
Overall Survival
Time, in days, from informed consent date until the date of death or date of last contact
Time frame: unlimited
Population: Based on the first date of CR or CRi to date of documented relapse, death, or subsequent chemotherapies including hematopoietic stem cell transplant (HSCT)(n=10)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Marqibo | Overall Survival | 56 days |