B-Cell Acute Lymphoblastic Leukemia, Adult
Conditions
Keywords
blinatumomab, pembrolizumab, MK-3475, relapsed, refractory, B-lineage acute lymphoblastic leukemia, ALL
Brief summary
This is a Phase I/II study of blinatumomab in combination with pembrolizumab in adult patients with relapsed or refractory B-lineage ALL (B-ALL). The primary objective of this study is to determine if the addition of pembrolizumab to blinatumomab improves the Complete Response Rate (CR) and Complete Remission with Partial Hematologic Recovery (CRh) relative to blinatumomab alone in adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia with high bone marrow lymphoblast percentage (\>50% lymphoblasts).
Detailed description
This is a Phase I/II study of blinatumomab in combination with pembrolizumab in adult patients with relapsed or refractory B-lineage ALL (B-ALL). The primary objective of this study is to determine if the addition of pembrolizumab to blinatumomab improves the Complete Response Rate (CR) and Complete Remission with Partial Hematologic Recovery (CRh) relative to blinatumomab alone in adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia with high bone marrow lymphoblast percentage (\>50% lymphoblasts). Mechanisms of resistance to blinatumomab are not well understood although inhibition of or suboptimal T-cell activation may play an important role. Programmed Death-Ligand 1 (PD-L1) and Programmed Death-Ligand 2 (PD-L2) expression and upregulation in lymphoblasts and the bone marrow microenvironment at baseline and in response to cytokines including those released upon blinatumomab exposure may inhibit T-cell function through the Programmed Death 1 (PD-1) receptor and lead to resistance to blinatumomab. The investigators hypothesize that part of the resistance to therapy with blinatumomab is mediated by the exuberant cytokine release seen with higher disease burden leading to increased expression of PD-L1 and PD-L2. Enhancing T-cell activity through use of the PD-1 inhibitor pembrolizumab is predicted to augment the activity of blinatumomab and convert more patients to complete remission and prolong remission durations. This study will also act to expand knowledge of PD-L1 and PD-L2 dynamics in response to blinatumomab. It will also be a paradigm for the addition of checkpoint inhibitors to therapy with bifunctional T-cell engaging antibodies currently in development for targeting other liquid and solid tumors. The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention. Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the Immunoglobulin G4 (IgG4/kappa) isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The study will be conducted in 2 stages: Stage 1 is to ensure safety of pembrolizumab in combination with blinatumomab. Stage 2 of the study will include an expansion cohort of up to 21 additional subjects (for a total of 24 subjects) to evaluate the efficacy of the combination of blinatumomab and pembrolizumab in adults with relapsed/refractory B-cell ALL
Interventions
DRUGblinatumomab
Cycle 1 Blinatumomab Day 1-7 Continuous IV infusion for 28 days (9 mcg/day) Blinatumomab Day 8-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle 2-5 Blinatumomab Day 1-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle length 42 days
DRUGpembrolizumab
Cycle 1 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg) Cycle 2-5 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg)
Sponsors
Merck Sharp & Dohme LLC
Amgen
University of California, San Diego
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
* Relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL) having received at least 1 prior line of therapy * Philadelphia chromosome positive (Ph+), or Breakpoint Cluster Region Protein-Abelson Murine Leukemia Viral Oncogene Homolog 1 (BCR-ABL1) positive B-lineage ALL must have failed at least 1 second or third generation tyrosine kinase inhibitor (TKI) or be intolerant to TKIs * Greater than 50% lymphoblasts on screening bone marrow aspirate or biopsy * Adequate organ function * Women of child-bearing potential and men with partners of child-bearing potential must agree to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. * A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) * Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential even if they have had a successful vasectomy starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Exclusion criteria
* Allogeneic hematopoietic cell transplantation within 5 years of study drug administration * Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. * Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) or Granulocyte Colony-Stimulating Factor (G-CSF) use within 2 weeks of study treatment and throughout the study * Prior checkpoint inhibitor therapy including anti Programmed Death Receptor 1 (anti-PD1), anti-PD-L1, anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4), anti tumor necrosis factor receptor superfamily, member 9 (anti-CD137), or anti-PD-L2 therapy * Active Central Nervous System (CNS) or testicular involvement by leukemia * History of neurologic disorder * Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. * Burkitt lymphoma/leukemia * Has a diagnosis of congenital immunodeficiency * Has a known history of active Bacillus Tuberculosis (TB) * Known Human Immunodeficiency Virus (HIV) infection * Active hepatitis B or hepatitis C infection * Has received a live vaccine within 30 days prior to first dose * Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. * History of autoimmune disease * Known interstitial lung disease * Any evidence of active, non-infectious pneumonitis or has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis * Patients who have received chemotherapy or radiotherapy within 2 weeks prior to entering the study or has not recovered from adverse events due to agents administered more than 2 weeks earlier. * Patients who are less than 4 weeks from surgery or have insufficient recovery from surgical-related trauma or wound healing. * Known impaired cardiac function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (ORR) | 28 weeks | Best overall response rate (ORR) with the combination of blinatumomab and pembrolizumab in adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia will be defined as the Complete Response (CR) rate plus the Complete Response with Hematologic Recovery (CRh) rate after treatment of combination therapy. According to the National Comprehensive Cancer Network (NCCN) Guidelines for Acute Lymphoblastic Leukemia (version 1, 2015), CR is defined as \<5% lymphoblast in the bone marrow without evidence of circulating lymphoblasts or extramedullary disease. CRh is defined as for CR except with platelet count \>50,000/microliter, hemoglobin \>7 g/dL, and neutrophil (ANC) \>500/microliter. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CR) | 28 weeks | CR is defined as \<5% lymphoblast in the bone marrow without evidence of circulating lymphoblasts or extramedullary disease. |
| Minimal Residual Disease (MRD) Negativity Rate in Subjects Achieving a CR or CRh | 28 weeks | Minimal residual disease (MRD) negativity in subjects achieving a CR or CRh will be defined as less than 0.01% residual lymphoblasts by multiparameter flow cytometry. |
| 2 Year Relapse-free Survival Rate | 2 years | The number of patients achieving relapse free survival at 2 years. Relapse-free survival (RFS) will be defined as the time from achieving CR or CRh to relapse defined as the reappearance of lymphoblasts in bone marrow or blood at \>5% of cells or reappearance of extramedullary disease. |
| 2-year Overall Survival Rate | 2 years | The number of participants achieving survival at 2 years. 2-year overall survival (OS) will be defined as the time from starting study therapy to death from any cause. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Blinatumomab + Pembrolizumab Drug: blinatumomab Cycle 1 Blinatumomab Day 1-7 Continuous IV infusion for 28 days (9 mcg/day) Blinatumomab Day 8-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle 2-5 Blinatumomab Day 1-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle length 42 days
Other Names:
Blincyto Drug: pembrolizumab Cycle 1 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg) Cycle 2-5 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg)
Other Names:
Keytruda MK-3475 blinatumomab: Cycle 1 Blinatumomab Day 1-7 Continuous IV infusion for 28 days (9 mcg/day) Blinatumomab Day 8-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle 2-5 Blinatumomab Day 1-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle length 42 days pembrolizumab: Cycle 1 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg) Cycle 2-5 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg) | 12 |
| Blinatumomab Only Patients did not receive Pembrolizumab due to early termination | 4 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Disease Progression | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Blinatumomab + Pembrolizumab | Blinatumomab Only | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 3 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 2 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Female | 8 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 12 | 0 / 4 |
| other Total, other adverse events | 12 / 12 | 4 / 4 |
| serious Total, serious adverse events | 4 / 12 | 1 / 4 |
Outcome results
Primary
Best Overall Response Rate (ORR)
Best overall response rate (ORR) with the combination of blinatumomab and pembrolizumab in adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia will be defined as the Complete Response (CR) rate plus the Complete Response with Hematologic Recovery (CRh) rate after treatment of combination therapy. According to the National Comprehensive Cancer Network (NCCN) Guidelines for Acute Lymphoblastic Leukemia (version 1, 2015), CR is defined as \<5% lymphoblast in the bone marrow without evidence of circulating lymphoblasts or extramedullary disease. CRh is defined as for CR except with platelet count \>50,000/microliter, hemoglobin \>7 g/dL, and neutrophil (ANC) \>500/microliter.
Time frame: 28 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Blinatumomab + Pembrolizumab | Best Overall Response Rate (ORR) | Complete Response with Hematologic Recovery | 1 Participants |
| Blinatumomab + Pembrolizumab | Best Overall Response Rate (ORR) | Refractory | 4 Participants |
| Blinatumomab + Pembrolizumab | Best Overall Response Rate (ORR) | Partial Response | 1 Participants |
| Blinatumomab + Pembrolizumab | Best Overall Response Rate (ORR) | Not Evaluated | 0 Participants |
| Blinatumomab + Pembrolizumab | Best Overall Response Rate (ORR) | Complete Response (CR) | 6 Participants |
| Blinatumomab Only | Best Overall Response Rate (ORR) | Not Evaluated | 3 Participants |
| Blinatumomab Only | Best Overall Response Rate (ORR) | Complete Response (CR) | 0 Participants |
| Blinatumomab Only | Best Overall Response Rate (ORR) | Complete Response with Hematologic Recovery | 0 Participants |
| Blinatumomab Only | Best Overall Response Rate (ORR) | Partial Response | 0 Participants |
| Blinatumomab Only | Best Overall Response Rate (ORR) | Refractory | 1 Participants |
Secondary
2-year Overall Survival Rate
The number of participants achieving survival at 2 years. 2-year overall survival (OS) will be defined as the time from starting study therapy to death from any cause.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab + Pembrolizumab | 2-year Overall Survival Rate | 3 participants |
| Blinatumomab Only | 2-year Overall Survival Rate | 1 participants |
Secondary
2 Year Relapse-free Survival Rate
The number of patients achieving relapse free survival at 2 years. Relapse-free survival (RFS) will be defined as the time from achieving CR or CRh to relapse defined as the reappearance of lymphoblasts in bone marrow or blood at \>5% of cells or reappearance of extramedullary disease.
Time frame: 2 years
Population: All participants who achieved a CR or CRh response were in the Blinatumomab + Pembrolizumab group. No participants in the Pembrolizumab Only group achieved a CR or CRh.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab + Pembrolizumab | 2 Year Relapse-free Survival Rate | 2 participants |
Secondary
Complete Response Rate (CR)
CR is defined as \<5% lymphoblast in the bone marrow without evidence of circulating lymphoblasts or extramedullary disease.
Time frame: 28 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Blinatumomab + Pembrolizumab | Complete Response Rate (CR) | 6 Participants |
| Blinatumomab Only | Complete Response Rate (CR) | 0 Participants |
Secondary
Minimal Residual Disease (MRD) Negativity Rate in Subjects Achieving a CR or CRh
Minimal residual disease (MRD) negativity in subjects achieving a CR or CRh will be defined as less than 0.01% residual lymphoblasts by multiparameter flow cytometry.
Time frame: 28 weeks
Population: 7 participants received both Blinatumomab and Pembrolizumab and achieved a CR or CRh. Of the 7, 6 had achieved MRD negativity and 1 had unevaluable data. 2 participants received only Blinatumomab and achieved a CR or CRh, but neither had evaluable MRD data.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Blinatumomab + Pembrolizumab | Minimal Residual Disease (MRD) Negativity Rate in Subjects Achieving a CR or CRh | MRD negativity | 6 Participants |
| Blinatumomab + Pembrolizumab | Minimal Residual Disease (MRD) Negativity Rate in Subjects Achieving a CR or CRh | MRD not evaluable | 1 Participants |
| Blinatumomab Only | Minimal Residual Disease (MRD) Negativity Rate in Subjects Achieving a CR or CRh | MRD negativity | 0 Participants |
| Blinatumomab Only | Minimal Residual Disease (MRD) Negativity Rate in Subjects Achieving a CR or CRh | MRD not evaluable | 2 Participants |