Blinatumomab and Pembrolizumab for Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia With High Marrow Lymphoblasts

Sponsor

University of California, San Diego (Other)

Overall Status

Terminated

CT.gov ID

NCT03160079

Collaborator

Merck Sharp & Dohme LLC (Industry), Amgen (Industry)

Enrollment

Locations

Arm

56.5

Actual Duration (Months)

4.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 The primary objective of this study is to determine if the addition of pembrolizumab to blinatumomab improves the overall response rate (CR+ 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).

Condition or Disease	Intervention/Treatment	Phase
B-Cell Acute Lymphoblastic Leukemia, Adult	Drug: blinatumomab Drug: pembrolizumab	Phase 1/Phase 2

Detailed Description

Mechanisms of resistance to blinatumomab are not well understood although inhibition of or suboptimal T-cell activation may play an important role. PD-L1 and 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 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 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

Study Design

Study Type:

Interventional

Actual Enrollment :

14 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of Blinatumomab in Combination With Pembrolizumab (MK-3475) for Adults With Relapsed or Refractory B-lineage Acute Lymphoblastic Leukemia With High Bone Marrow Lymphoblast Percentage

Actual Study Start Date :

Aug 4, 2017

Actual Primary Completion Date :

Apr 19, 2022

Actual Study Completion Date :

Apr 19, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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 Pembroluzumab Day 15 and 36 IV infusion over 30 minutes (200mg) Cycle 2-5 Pembroluzumab Day 15 and 36 IV infusion over 30 minutes (200mg) Other Names: Keytruda, MK-3475

Arm

Intervention/Treatment

Experimental: 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 Pembroluzumab Day 15 and 36 IV infusion over 30 minutes (200mg) Cycle 2-5 Pembroluzumab Day 15 and 36 IV infusion over 30 minutes (200mg)

Other Names:

Keytruda, MK-3475

Outcome Measures

Primary Outcome Measures

Overall Response Rate (ORR) [28 weeks]

Secondary Outcome Measures

Complete Response Rate (CR) [28 weeks]
Minimal residual disease (MRD) negativity rate in subjects achieving a CR or CRh [28 weeks]
2 year relapse-free survival [2 years]
2-year overall survival [2 years]
Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.0 [4 years]
Safety and tolerability of blinatumomab in combination with pembrolizumab

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Relapsed or refractory B-lineage acute lymphoblastic leukemia having received at least 1 prior line of therapy
Philadelphia chromosome/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.
GM-CSF or G-CSF use within 2 weeks of study treatment and throughout the study
Prior checkpoint inhibitor therapy including anti-PD1, anti-PD-L1, anti-CTLA4, anti- CD137, or anti-PD-L2 therapy
Active 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 TB (Bacillus Tuberculosis)
Known 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
2	UC Irvine Health Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
3	UCSF Comprehensive Cancer Center	San Francisco	California	United States	94143