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

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ClinicalTrials.gov Identifier: NCT03160079
Recruitment Status : Recruiting
First Posted : May 19, 2017
Last Update Posted : September 24, 2018
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Amgen
Information provided by (Responsible Party):
Matthew Wieduwilt, M.D., Ph.D., University of California, San Diego

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:

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.

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
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 : August 4, 2017
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : August 2022


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 Name: 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 Name: Keytruda, MK-3475




Primary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 28 weeks ]

Secondary Outcome Measures :
  1. Complete Response Rate (CR) [ Time Frame: 28 weeks ]
  2. Minimal residual disease (MRD) negativity rate in subjects achieving a CR or CRh [ Time Frame: 28 weeks ]
  3. 2 year relapse-free survival [ Time Frame: 2 years ]
  4. 2-year overall survival [ Time Frame: 2 years ]
  5. Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.0 [ Time Frame: 4 years ]
    Safety and tolerability of blinatumomab in combination with pembrolizumab



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03160079


Contacts
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Contact: Jesika Reiner, MPH 858-822-5364 jreiner@ucsd.edu

Locations
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United States, California
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Matthew Wieduwilt, MD    858-822-6600    mwieduwilt@ucsd.edu   
UC Irvine Health Chao Family Comprehensive Cancer Center Recruiting
Orange, California, United States, 92868
Contact: Deepa Jeyakumar, MD    888-544-8235    djeyakum@uci.edu   
UCSF Comprehensive Cancer Center Not yet recruiting
San Francisco, California, United States, 94143
Contact: Lloyd Damon, MD    415-353-2737    damonl@medicine.ucsf.edu   
Sponsors and Collaborators
Matthew Wieduwilt, M.D., Ph.D.
Merck Sharp & Dohme Corp.
Amgen
Investigators
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Principal Investigator: Matthew Wieduwilt, M.D., P.h.D. University of California, San Diego

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Responsible Party: Matthew Wieduwilt, M.D., Ph.D., Assistant Clinical Professor of Medicine, University of California, San Diego
ClinicalTrials.gov Identifier: NCT03160079     History of Changes
Other Study ID Numbers: 161287/UCHMC1504
First Posted: May 19, 2017    Key Record Dates
Last Update Posted: September 24, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Matthew Wieduwilt, M.D., Ph.D., University of California, San Diego:
blinatumomab
pembrolizumab
MK-3475
relapsed
refractory
B-lineage acute lymphoblastic leukemia
ALL

Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Burkitt Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoma
Pembrolizumab
Blinatumomab
Antibodies, Bispecific
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs