A Phase I-II Study of the Combination of Ruxolitinib or Dasatinib With Chemotherapy in Patients With Philadelphia Chromosome (Ph)-Like Acute Lymphoblastic Leukemia (ALL)
Overview
- Phase
- Phase 2
- Intervention
- Cyclophosphamide
- Conditions
- Recurrent B Acute Lymphoblastic Leukemia
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 11
- Locations
- 1
- Primary Endpoint
- Maximal Tolerated Dose (MTD) of Ruxolitinib in Combination With Chemotherapy Defined as the Highest Dose Level at Which no More Than 1 Out of 6 Patients Experience a Dose Limiting Toxicity (Phase I)
- Status
- Terminated
- Last Updated
- 10 months ago
Overview
Brief Summary
This phase II trial studies the side effects and best dose of ruxolitinib phosphate and how well it works compared to dasatinib when given with chemotherapy in treating patients with Philadelphia chromosome-like acute lymphoblastic leukemia that has come back (relapsed) or has not responded to treatment (refractory). Ruxolitinib phosphate and dasatinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving ruxolitinib phosphate or dasatinib with chemotherapy works better in treating patients with previously treated acute lymphoblastic leukemia.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety and maximal tolerated dose (MTD) of ruxolitinib phosphate (ruxolitinib) in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL). (Phase I, ruxolitinib cohort only) II. To determine the response rate (complete response \[CR\]/CR with incomplete marrow recovery \[CRi\]) of ruxolitinib or dasatinib in combination with chemotherapy in patients with Ph-like ALL. (Phase II) SECONDARY OBJECTIVES: I. To determine the response rate (CR/CRi) of ruxolitinib in combination with chemotherapy in patients with Ph-like ALL. (Phase I, ruxolitinib cohort only) II. To determine the duration of response, disease-free survival and overall survival of ruxolitinib in combination with chemotherapy in patients with Ph-like ALL. (Phase I, ruxolitinib cohort only) III. To determine the safety and toxicity profile of ruxolitinib or dasatinib in combination with chemotherapy in patients with Ph-like ALL. (Phase II) IV. To determine the duration of response, disease-free survival and overall survival of ruxolitinib or dasatinib in combination with chemotherapy in patients with Ph-like ALL. (Phase II) OUTLINE: This is a phase I, dose escalation study of ruxolitinib followed by a phase II study. Patients are assigned to 1 of 2 cohorts. COHORT A: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. COHORT B: Patients receive dasatinib PO once daily (QD). Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. INTENSIVE CHEMOTHERAPY: After cycle 1, patients not achieving a response also receive cyclophosphamide intravenously (IV) over 3 hours BID on days 1-3, doxorubicin IV over 24-48 hours on day 4, vincristine IV over 30 minutes on days 4 and 11, and dexamethasone PO QD or IV over 30 minutes on days 1-4 and 11-14 of cycles 1, 3, 5, and 7. Patients receive methotrexate IV over 24 hours on day 1, leucovorin IV over 1 hour or PO every 6 hours on days 2-5, cytarabine IV over 2 hours BID on days on days 2 and 3 of cycles 2, 4, 6, and 8. At the discretion of the treating physician, patients may also receive rituximab IV over several hours on days 1 and 11 of cycles 1 and 3 and on days 1 and 8 of cycles 2 and 4 only. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive mercaptopurine PO thrice daily (TID), methotrexate PO once a week, vincristine IV over 30 minutes on day 1, and prednisone PO on days 1-5. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients with previously treated B-cell ALL (relapsed and/or refractory after prior therapy)
- •Bone marrow involvement with \>= 5% lymphoblasts
- •Documented genetic lesion(s) known to confer susceptibility to inhibition by either ruxolitinib or dasatinib or cytokine receptor-like factor 2 (CRLF2) positivity by flow cytometry (for the ruxolitinib cohort)
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
- •Total bilirubin \< 2.0 mg/dL
- •Serum glutamate pyruvate transaminase (SGPT) or serum glutamic oxaloacetic transaminase (SGOT) \< 3 x upper limit of normal (ULN)
- •Creatinine \< 2 mg/dL
- •Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy; appropriate methods of birth control include the following: any 2 of the following methods used together: birth control implants, injections, or pills (except for progesterone only pills), intrauterine device (IUD), vasectomy, tubal ligation, barrier method (female or male condom with spermicide, cervical cap with spermicide, diaphragm with spermicide); male condom with spermicide and diaphragm; male condom with spermicide and cervical cap; unacceptable methods of birth control include using no birth control, withdrawal, rhythm method, vaginal sponge, any barrier method that does not use spermicide, progesterone only pills, and using male and female condoms at the same time
- •Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug
- •Patients or their legally authorized representative must provide written informed consent
Exclusion Criteria
- •Burkitt's leukemia or lymphoma, T-cell ALL or lymphoblastic lymphoma
- •Patients having undergone prior allogeneic stem cell transplant within 3 months or having active graft versus host disease
- •Patient is pregnant or breastfeeding
- •Patients with uncontrolled active infections (fever \>= 38 degrees Celsius \[C\], septic shock)
- •Isolated extramedullary relapse (i.e. testicular, central nervous system)
- •Current or chronic hepatitis B or C infection, or known seropositivity for human immunodeficiency virus (HIV)
- •Concurrent chemotherapy (except intrathecal chemotherapy)
- •Major surgery within 4 weeks prior to first study dose
- •Systemic chemotherapy/radiotherapy/investigational therapy within 14 days (with the exception of hydroxyurea and steroids) prior to starting therapy; for patients receiving ALL maintenance with 6-mercaptopurine, methotrexate, vincristine, and steroids - these agents should be discontinued at least 48 hours prior to start of study drugs; for patients on oral targeted therapies (such as imatinib, dasatinib, ponatinib), - these agents should be discontinued at least 48 hours prior to start of study drugs
- •Patients must have recovered from acute non hematologic toxicity (to =\< grade 1) of all previous therapy prior to enrollment
Arms & Interventions
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cytarabine
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Dexamethasone
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Leucovorin
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Mercaptopurine
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Methotrexate
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Prednisone
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Rituximab
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Ruxolitinib Phosphate
Cohort A (ruxolitinib phosphate)
Patients receive ruxolitinib phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Vincristine
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cytarabine
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Dasatinib
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Dexamethasone
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Leucovorin
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Mercaptopurine
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Methotrexate
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Prednisone
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Rituximab
Cohort B (dasatinib)
Patients receive dasatinib PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Vincristine
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Cytarabine
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Dexamethasone
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Leucovorin
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Mercaptopurine
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Methotrexate
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Prednisone
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Rituximab
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Ruxolitinib Phosphate
Phase 1
Patients Receive ruxolitinib Phosphate PO BID. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Vincristine
Outcomes
Primary Outcomes
Maximal Tolerated Dose (MTD) of Ruxolitinib in Combination With Chemotherapy Defined as the Highest Dose Level at Which no More Than 1 Out of 6 Patients Experience a Dose Limiting Toxicity (Phase I)
Time Frame: 42 days
The method of Thall, Simon and Estey will be used for toxicity monitoring for this study. The severity of the toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 whenever possible. Safety data will be summarized by category, severity and frequency.
Participants With Complete Response (Complete Response [CR]/CR With Incomplete Marrow Recovery [CRi]) (Phase II)
Time Frame: 42 days
Complete Response (CR) is disappearance of all clinical and/or radiologic evidence of disease, Neutrophil count ≥ 1.0 x 10\^9/L, Platelet count ≥ 100 x 10\^9/L, Normal bone marrow differential (≤ 5% blasts), No extra-medullary leukemia. Complete Remission with Incomplete Blood Count Recovery (CRi) is CR except for ANC \< 1.0 x 10\^9/L and/or platelets \< 100 x 10\^9/L.
Secondary Outcomes
- Progression-free Survival(Up to 4 years 7 months)
- Overall Survival(Up to 4 years 7 months)