Acute Myeloid Leukemia, Higher Risk Myelodysplastic Syndrome
Conditions
Keywords
AML, MDS
Brief summary
This is a phase II trial of nivolumab and low dose cyclophosphamide (CTX) when given in combination to patients with relapsed/refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS) who are not eligible for or decline hematopoietic stem cell transplant. It includes a randomized pilot sub-study during stage 1.
Interventions
DRUGNivolumab
3mg/kg IV (or if prior alloHSCT, 1 mg/kg) over 30 minutes every 14 days on Days 1 and 15 for up to four 28-day courses.
DRUGLow dose Cyclophosphamide (CTX) Daily
Oral cyclophosphamide 50mg + nivolumab 3 mg/kg IV every 2 weeks for up to 4 courses of treatment
DRUGLow dose Cyclophosphamide (CTX) Every 7 Days
Oral cyclophosphamide 350 mg every 7 days + nivolumab 3mg/kg IV every 2 weeks for up to 4 courses of treatment
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥18 years of age * Meets one of the following disease criteria: * Primary (de novo) AML or higher-risk MDS with induction failure: No CR after 2 or more induction attempts with high dose chemotherapy or hypomethylating agents or other agents; no CR after 1 induction attempt and not eligible for a 2nd induction.. Higher risk MDS defined as risk score \> 4.5 based on the revised IPSS criteria. * Secondary AML (from antecedent hematologic malignancy or treatment-related): Not in CR after 1 or more cycles of chemotherapy. * Relapsed AML: Blasts ≥5% in bone marrow or peripheral blood after prior attainment of CR; relapse at any time but currently ≥100 days following allogeneic HCT. * Relapsed MDS: Morphologic evidence of relapse or increase in blasts ≥5% in bone marrow or peripheral blood after prior attainment of hematologic improvement; or partial or complete response ; relapse at any time but currently ≥100 days following allogeneic HCT.. * ECOG Performance Status ≤ 2 - refer to Appendix II * Adequate organ function within 14 days of study registration defined as: * Absolute Lymphocyte Count: ≥ 500 cells/mm3 * Hepatic: total bilirubin ≤ 3 x upper limit of institutional normal (ULN); ALT and AST ≤ 5 x ULN * Renal: Serum creatinine ≤ 2 mg/dL * Pulmonary: No oxygen requirement on room air or requiring ≤ 2L supplemental O2 * Sexually active females of child bearing potential and males with partners of child bearing potential must agree to use effective contraception during therapy and continuing (23 weeks for females, 31 weeks for males) after the last dose of nivolumab * Voluntary written consent
Exclusion criteria
* Pregnant or breastfeeding -The agents used in this study fall under Pregnancy Category D - Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. Women of childbearing potential must have a negative pregnancy test (urine or serum) within 7 days of study drug administration. * Prior allogeneic hematopoietic stem cell transplantation within previous 100 days (note patients with a prior alloHSCT receive nivolumab at the reduced dose of 1 mg/kg) * Signs or symptoms of active graft versus host disease * Active pneumonitis or uncontrolled infection * Received chemotherapy drugs within previous 2 weeks * Estimated life expectancy \<28 days in the opinion of the enrolling investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1: Dosing Schedule of Low-dose Cyclophosphamide | 4 weeks from start of treatment | Number of participants with adverse events |
| Clinical Benefit and Immunologic Response of the Combination Therapy | 90 days from start of treatment | Overall response rate at 90 days from treatment start. Response is defined as CR + CRi + CRp + PR in AML and CR/PR/hematologic improvement (HI) in MDS. Complete Remission (CR) - subjects must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state, an ANC \> 1 x 109/L and platelet count ≥ 100 x 109/L and normal marrow differential with \< 5% blasts, and they will be RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia Complete Remission with Incomplete Hematologic Recovery (CRi) - subjects must fulfill all the criteria for CR except for incomplete hematological recovery Complete Remission with Incomplete Platelet Recovery (CRp) - subjects must achieve CR except for incomplete platelet recovery Partial Remission (PR) - subjects must have ≥50% bone marrow blast reduction or decrease to 5 to 25% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 30 days from start of treatment | Incidence of overall response. |
| Progression Free Survival (PFS) | 6 months from start of treatment | Incidence of progression free survival. |
| Overall Survival (OS) | 6 months from start of treatment | Incidence of overall survival. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily Nivolumab: 3mg/kg IV (or if prior alloHSCT, 1 mg/kg) over 30 minutes every 14 days on Days 1 and 15 for up to four 28-day courses.
Low dose Cyclophosphamide (CTX): Oral cyclophosphamide 50mg + nivolumab 3 mg/kg IV every 2 weeks for up to 4 courses of treatment | 6 |
| Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days Nivolumab: 3mg/kg IV (or if prior alloHSCT, 1 mg/kg) over 30 minutes every 14 days on Days 1 and 15 for up to four 28-day courses.
Low dose Cyclophosphamide (CTX): Oral cyclophosphamide 350 mg every 7 days + nivolumab 3mg/kg IV every 2 weeks for up to 4 courses of treatment | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily | Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 4 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 11 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 1 / 6 |
| other Total, other adverse events | 4 / 6 | 6 / 6 |
| serious Total, serious adverse events | 3 / 6 | 5 / 6 |
Outcome results
Primary
Clinical Benefit and Immunologic Response of the Combination Therapy
Overall response rate at 90 days from treatment start. Response is defined as CR + CRi + CRp + PR in AML and CR/PR/hematologic improvement (HI) in MDS. Complete Remission (CR) - subjects must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state, an ANC \> 1 x 109/L and platelet count ≥ 100 x 109/L and normal marrow differential with \< 5% blasts, and they will be RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia Complete Remission with Incomplete Hematologic Recovery (CRi) - subjects must fulfill all the criteria for CR except for incomplete hematological recovery Complete Remission with Incomplete Platelet Recovery (CRp) - subjects must achieve CR except for incomplete platelet recovery Partial Remission (PR) - subjects must have ≥50% bone marrow blast reduction or decrease to 5 to 25%
Time frame: 90 days from start of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily | Clinical Benefit and Immunologic Response of the Combination Therapy | 0 Participants |
| Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days | Clinical Benefit and Immunologic Response of the Combination Therapy | 0 Participants |
Primary
Stage 1: Dosing Schedule of Low-dose Cyclophosphamide
Number of participants with adverse events
Time frame: 4 weeks from start of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily | Stage 1: Dosing Schedule of Low-dose Cyclophosphamide | 6 Participants |
| Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days | Stage 1: Dosing Schedule of Low-dose Cyclophosphamide | 6 Participants |
Secondary
Objective Response Rate (ORR)
Incidence of overall response.
Time frame: 30 days from start of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily | Objective Response Rate (ORR) | 0 Participants |
| Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days | Objective Response Rate (ORR) | 0 Participants |
Secondary
Overall Survival (OS)
Incidence of overall survival.
Time frame: 6 months from start of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily | Overall Survival (OS) | 4 Participants |
| Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days | Overall Survival (OS) | 5 Participants |
Secondary
Progression Free Survival (PFS)
Incidence of progression free survival.
Time frame: 6 months from start of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Nivolumab Every 2 Weeks and Cyclophosphamide Daily | Progression Free Survival (PFS) | 0 Participants |
| Arm 2: Nivolumab Every 2 Weeks and Cyclophosphamide Every 7 Days | Progression Free Survival (PFS) | 0 Participants |