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Open Label Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab (KEYNOTE-348)

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ClinicalTrials.gov Identifier: NCT03340766
Recruitment Status : Recruiting
First Posted : November 14, 2017
Last Update Posted : December 14, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Amgen

Brief Summary:
Phase 1b: To determine the maximum tolerated dose (MTD) of blinatumomab in combination with pembrolizumab in adult subjects with relapsed or refractory (r/r) DLBCL

Condition or disease Intervention/treatment Phase
Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL) Drug: Blinatumomab Drug: Pembrolizumab Phase 1

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Open Label Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adult Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL) (KEYNOTE-348)
Actual Study Start Date : March 16, 2018
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : October 5, 2024


Arm Intervention/treatment
Experimental: COHORT Ib
Blinatumomab 9 to 28 microgram plus Pembrolizumab (day 1).
Drug: Blinatumomab

Up to 2 cycles of Blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion. The dosing given is dependent on the cohort, and is as follows:

Cohort Ia/b: 9 microgram/day for 7 days followed by 28 microgram/day for the remainder of each cycle.

Cohort IIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 112 microgram/day for the remainder of each cycle.

Cohort IIIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 56 microgram/day for the remainder of each cycle.

The Maximum Tolerated Dose identified through this cohort design will then be tested in the expansion cohort.

Other Names:
  • BlinCyto
  • AMG 103
  • Formerly known as MT103 or bscCD19xCD3

Drug: Pembrolizumab

One cycle of Pembrolizumab is a 200 milligrams intravenous injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.

Treatment start is dependent on the cohort:

Cohort Ia: Study day 15 (where blinatumomab treatment started on study day 1) Cohort IIb, IIb, IIIb: Study day 1 (where blinatumomab treatment also starts on study day 1) Cohort IIa, IIIa: Study day 19 (where blinatumomab treatment stated on study day 1)

Other Name: Keytruda

Experimental: COHORT IIb
Blinatumomab 9 to 28 to 112 microgram plus Pembrolizumab (day 1).
Drug: Blinatumomab

Up to 2 cycles of Blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion. The dosing given is dependent on the cohort, and is as follows:

Cohort Ia/b: 9 microgram/day for 7 days followed by 28 microgram/day for the remainder of each cycle.

Cohort IIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 112 microgram/day for the remainder of each cycle.

Cohort IIIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 56 microgram/day for the remainder of each cycle.

The Maximum Tolerated Dose identified through this cohort design will then be tested in the expansion cohort.

Other Names:
  • BlinCyto
  • AMG 103
  • Formerly known as MT103 or bscCD19xCD3

Drug: Pembrolizumab

One cycle of Pembrolizumab is a 200 milligrams intravenous injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.

Treatment start is dependent on the cohort:

Cohort Ia: Study day 15 (where blinatumomab treatment started on study day 1) Cohort IIb, IIb, IIIb: Study day 1 (where blinatumomab treatment also starts on study day 1) Cohort IIa, IIIa: Study day 19 (where blinatumomab treatment stated on study day 1)

Other Name: Keytruda

Experimental: COHORT IIIb
Blinatumomab 9 to 28 to 56 microgram plus Pembrolizumab (day 1).
Drug: Blinatumomab

Up to 2 cycles of Blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion. The dosing given is dependent on the cohort, and is as follows:

Cohort Ia/b: 9 microgram/day for 7 days followed by 28 microgram/day for the remainder of each cycle.

Cohort IIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 112 microgram/day for the remainder of each cycle.

Cohort IIIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 56 microgram/day for the remainder of each cycle.

The Maximum Tolerated Dose identified through this cohort design will then be tested in the expansion cohort.

Other Names:
  • BlinCyto
  • AMG 103
  • Formerly known as MT103 or bscCD19xCD3

Drug: Pembrolizumab

One cycle of Pembrolizumab is a 200 milligrams intravenous injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.

Treatment start is dependent on the cohort:

Cohort Ia: Study day 15 (where blinatumomab treatment started on study day 1) Cohort IIb, IIb, IIIb: Study day 1 (where blinatumomab treatment also starts on study day 1) Cohort IIa, IIIa: Study day 19 (where blinatumomab treatment stated on study day 1)

Other Name: Keytruda

Experimental: COHORT Ia
Blinatumomab 9 to 28 microgram plus Pembrolizumab (day 15).
Drug: Blinatumomab

Up to 2 cycles of Blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion. The dosing given is dependent on the cohort, and is as follows:

Cohort Ia/b: 9 microgram/day for 7 days followed by 28 microgram/day for the remainder of each cycle.

Cohort IIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 112 microgram/day for the remainder of each cycle.

Cohort IIIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 56 microgram/day for the remainder of each cycle.

The Maximum Tolerated Dose identified through this cohort design will then be tested in the expansion cohort.

Other Names:
  • BlinCyto
  • AMG 103
  • Formerly known as MT103 or bscCD19xCD3

Drug: Pembrolizumab

One cycle of Pembrolizumab is a 200 milligrams intravenous injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.

Treatment start is dependent on the cohort:

Cohort Ia: Study day 15 (where blinatumomab treatment started on study day 1) Cohort IIb, IIb, IIIb: Study day 1 (where blinatumomab treatment also starts on study day 1) Cohort IIa, IIIa: Study day 19 (where blinatumomab treatment stated on study day 1)

Other Name: Keytruda

Experimental: COHORT IIa
Blinatumomab 9 to 28 to 112 microgram plus Pembrolizumab (day 19).
Drug: Blinatumomab

Up to 2 cycles of Blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion. The dosing given is dependent on the cohort, and is as follows:

Cohort Ia/b: 9 microgram/day for 7 days followed by 28 microgram/day for the remainder of each cycle.

Cohort IIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 112 microgram/day for the remainder of each cycle.

Cohort IIIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 56 microgram/day for the remainder of each cycle.

The Maximum Tolerated Dose identified through this cohort design will then be tested in the expansion cohort.

Other Names:
  • BlinCyto
  • AMG 103
  • Formerly known as MT103 or bscCD19xCD3

Drug: Pembrolizumab

One cycle of Pembrolizumab is a 200 milligrams intravenous injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.

Treatment start is dependent on the cohort:

Cohort Ia: Study day 15 (where blinatumomab treatment started on study day 1) Cohort IIb, IIb, IIIb: Study day 1 (where blinatumomab treatment also starts on study day 1) Cohort IIa, IIIa: Study day 19 (where blinatumomab treatment stated on study day 1)

Other Name: Keytruda

Experimental: COHORT IIIa
Blinatumomab 9 to 28 to 56 microgram plus Pembrolizumab (day 19).
Drug: Blinatumomab

Up to 2 cycles of Blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion. The dosing given is dependent on the cohort, and is as follows:

Cohort Ia/b: 9 microgram/day for 7 days followed by 28 microgram/day for the remainder of each cycle.

Cohort IIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 112 microgram/day for the remainder of each cycle.

Cohort IIIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 56 microgram/day for the remainder of each cycle.

The Maximum Tolerated Dose identified through this cohort design will then be tested in the expansion cohort.

Other Names:
  • BlinCyto
  • AMG 103
  • Formerly known as MT103 or bscCD19xCD3

Drug: Pembrolizumab

One cycle of Pembrolizumab is a 200 milligrams intravenous injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.

Treatment start is dependent on the cohort:

Cohort Ia: Study day 15 (where blinatumomab treatment started on study day 1) Cohort IIb, IIb, IIIb: Study day 1 (where blinatumomab treatment also starts on study day 1) Cohort IIa, IIIa: Study day 19 (where blinatumomab treatment stated on study day 1)

Other Name: Keytruda

Experimental: Expansion Cohort
This cohort will test the Maximum Tolerated Dose of Blinatumomab in combination with Pembrolizumab identified using cohort design from cohorts Ia/b, IIa/b and IIIa/b tested in Part 1 of the study.
Drug: Blinatumomab

Up to 2 cycles of Blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion. The dosing given is dependent on the cohort, and is as follows:

Cohort Ia/b: 9 microgram/day for 7 days followed by 28 microgram/day for the remainder of each cycle.

Cohort IIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 112 microgram/day for the remainder of each cycle.

Cohort IIIa/b: 9 microgram/day for 7 days followed by 28 microgram/day for 7 days followed by 56 microgram/day for the remainder of each cycle.

The Maximum Tolerated Dose identified through this cohort design will then be tested in the expansion cohort.

Other Names:
  • BlinCyto
  • AMG 103
  • Formerly known as MT103 or bscCD19xCD3

Drug: Pembrolizumab

One cycle of Pembrolizumab is a 200 milligrams intravenous injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.

Treatment start is dependent on the cohort:

Cohort Ia: Study day 15 (where blinatumomab treatment started on study day 1) Cohort IIb, IIb, IIIb: Study day 1 (where blinatumomab treatment also starts on study day 1) Cohort IIa, IIIa: Study day 19 (where blinatumomab treatment stated on study day 1)

Other Name: Keytruda




Primary Outcome Measures :
  1. Incidence of dose limiting toxicities (DLTs) [ Time Frame: Up to study day 63, depending on cohort dosing and schedule ]
    Incidence of dose limiting toxicities (DLTs) will be assessed during each cohort


Secondary Outcome Measures :
  1. Objective Response Rate [ Time Frame: Study week 10 and every 12 weeks thereafter, for up to 24 months ]
    Objective response rate (including Complete Response and Partial Response) by Cheson Criteria

  2. Progression Free Survival [ Time Frame: Study week 10 and every 12 weeks thereafter, for up to 24 months ]
    Progression Free Survival (PFS) by Cheson Criteria

  3. Overall Survival [ Time Frame: Subjects followed for survival up to 48 months (24 months after last dose of pembrolizumab) ]
    Overall Survival (OS) will be determined for 24 months following the last dose of pembrolizumab.

  4. Complete Response rate [ Time Frame: Study week 10 and every 12 weeks thereafter, for up to 24 months ]
    Complete Response (CR) rate by Cheson Criteria

  5. Duration of response [ Time Frame: Study week 10 and every 12 weeks thereafter, for up to 24 months ]
    The duration of response (DOR) will be determined using Objective response rate (ORR), Complete response (CR) and Partial Response (PR), and using Cheson Criteria

  6. Blinatumomab Steady state concentration [ Time Frame: Up to study day 43, depending on cohort dosing and schedule ]
    Pharmacokinetic profile of Blinatumomab: Steady state concentration (Css)

  7. Blinatumomab Clearance rate [ Time Frame: Up to study day 43, depending on cohort dosing and schedule ]
    Pharmacokinetic profile of Blinatumomab - Clearance rate

  8. Pembrolizumab Peak Plasma Concentration [ Time Frame: Up to 25 months ]
    Pembrolizumab Pharmacokinetic parameter: Peak Plasma Concentration (Cmx)

  9. Pembrolizumab Minimum plasma concentration [ Time Frame: Up to 25 months ]
    Pharmacokinetic profile of Pembrolizumab: Minumum plasma concentration (Cmn)

  10. Pembrolizumab PK Parameter - AUC [ Time Frame: Up to 25 months ]
    Pharmacokinetic profile of Pembrolizumab: Area under the plasma concentration versus time curve (AUC)


Other Outcome Measures:
  1. Incidence and severity of adverse events [ Time Frame: Up to 25 months ]
    Incidence and severity of adverse events

  2. Objective Response Rate [ Time Frame: Study week 10 and every 12 weeks thereafter, for up to 24 months ]
    By Lugano Classification. Exploratory.

  3. PD-L1 expression [ Time Frame: Up to study week 10 ]
    Programmed death ligand-1 (PD-L1) Exploratory

  4. Changes in Lymphocytes (B-cell, T-cell populations, NK cells) and leukocyte [ Time Frame: Up to study day 64 ]
    Exploratory

  5. Peripheral blood cytokine levels [ Time Frame: Up to study day 22 ]
    Exploratory. Monitor activation of immune effector cells by looking at Th1 and Th2 cytokines and others such as IL-6, IL-10, TNF alpha and INF gamma.

  6. Minimal Residual Disease [ Time Frame: Up to study week 10 ]
    Using Next Generation Sequencing. Exploratory

  7. Changes in Patient Reported Outcomes - EQ-5D. Exploratory. [ Time Frame: Up to 17 weeks ]
    EQ-5D. Exploratory.

  8. Changes in Patient Reported Outcomes - FACT-Lymphoma [ Time Frame: Up to 17 weeks ]
    FACT-Lymphoma



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have histologically confirmed Diffuse Large B Cell Lymphoma that is either:

    • Refractory to first or later treatment, or
    • First or later relapse AND has received at least 2 prior therapies (one of which can be frontline therapy) or
    • Relapsed post-autologous HSCT
  • Have measureable disease
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Life expectancy of ≥ 12 weeks in the opinion of the Investigator
  • Subject must be able to provide an evaluable core or excisional biopsy prior to the start of treatment. Other Inclusion Criteria May Apply

Exclusion Criteria:

  • Richter's transformation (DLBCL arising in the setting of prior chronic lymphocytic leukemia) or Primary Mediastinal B cell Lymphoma (PMBCL)
  • History or presence of clinically relevant Central Nervous System pathology such as epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of protocol specified therapy.
  • Has undergone prior allogeneic HSCT:

    • within the last 5 years OR
    • greater than 5 years ago but has active graft versus host disease (GvHD) requiring systemic treatment.
  • Has received autologous HSCT within 6 weeks prior to start of treatment. Other Exclusion Criteria May Apply.

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): NCT03340766


Contacts
Contact: Amgen Call Center 866-572-6436 medinfo@amgen.com

Locations
United States, South Carolina
Research Site Recruiting
Charleston, South Carolina, United States, 29424
Australia, New South Wales
Research Site Recruiting
Darlinghurst, New South Wales, Australia, 2010
Research Site Recruiting
St Leonards, New South Wales, Australia, 2065
Australia, South Australia
Research Site Recruiting
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Research Site Recruiting
East Melbourne, Victoria, Australia, 3002
Research Site Recruiting
Geelong, Victoria, Australia, 3220
Research Site Recruiting
Melbourne, Victoria, Australia, 3004
Australia, Western Australia
Research Site Recruiting
Murdoch, Western Australia, Australia, 6150
France
Research Site Recruiting
Créteil Cedex, France, 94010
Research Site Recruiting
Nantes Cedex 1, France, 44035
Research Site Recruiting
Pierre Benite Cedex, France, 69495
Sponsors and Collaborators
Amgen
Merck Sharp & Dohme Corp.
Investigators
Study Director: MD Amgen

Additional Information:
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT03340766     History of Changes
Other Study ID Numbers: 20150290
2016-002191-27 ( EudraCT Number )
First Posted: November 14, 2017    Key Record Dates
Last Update Posted: December 14, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
URL: https://www.amgen.com/datasharing

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

Keywords provided by Amgen:
DLBCL Relapsed post-autologous hematopoietic stem cell transplantation (HSCT)
Antibodies
Bispecific in combination with PD-1/PD-L1 inhibitor

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Pembrolizumab
Blinatumomab
Antibodies, Bispecific
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs