Carfilzomib and TGR-1202 in Treatment of R/R Lymphoma

Sponsor
Columbia University (Other)
Overall Status
Terminated
CT.gov ID
NCT02867618
Collaborator
(none)
14
Enrollment
1
Location
1
Arm
44.5
Actual Duration (Months)
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open label, phase I/II, dose-escalation study in the initial phase I followed by a phase II.

The primary objective of the phase I is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of TGR-1202 and carfilzomib in participants with relapsed and refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). The safety and toxicity of this combination will be evaluated throughout the entire study.

If the combination of TGR-1202 and carfilzomib is found to be feasible and an MTD is established, the phase II part of the study will be initiated.

Phase II will consist of a 2-stage design of the combination of TGR-1202 and carfilzomib for participants with R/R NHL.

Condition or DiseaseIntervention/TreatmentPhase
Phase 1/Phase 2

Detailed Description

Dysregulated c-Myc is associated with resistance to chemotherapy and poor survival in aggressive lymphomas. Novel strategies that target this biology could markedly improve the outcome of these participants. To date no drugs that directly target Myc have been approved for cancer treatment. Recent results by Deng et al. (Blood. 2017 Jan 5. PMID: 27784673) described a highly synergistic regimen discovered in preclinical models, through combining TGR-1202, an investigational drug that inhibits PI3K delta, and carfilzomib, a drug approved by the FDA for multiple myeloma. Importantly, the combination of TGR-1202 and carfilzomib acts by potently silencing the translation of c-Myc and inducing apoptosis in many cell lines and primary lymphoma cells representing broad histological subtypes of lymphoma. These results suggest that TGR-1202 and carfilzomib may be highly effective in relapsed and refractory lymphoma where c-Myc plays a key pathological role.

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:
Phase I/II Study of Carfilzomib and a PI3Kdelta Inhibitor TGR-1202 in the Treatment of Patients With Relapsed or Refractory Lymphoma
Actual Study Start Date :
Oct 16, 2016
Actual Primary Completion Date :
Jun 30, 2020
Actual Study Completion Date :
Jun 30, 2020

Arms and Interventions

ArmIntervention/Treatment
Experimental: Carfilzomib + TGR-1202

Oral TGR-1202 will be given PO once daily on Days 1-28 and carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle.

Drug: Carfilzomib
Carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. This will be in combination with the oral TGR-1202
Other Names:
  • Kyprolis
  • Drug: TGR-1202
    Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib
    Other Names:
  • (formerly) RP-5264
  • Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose (MTD) (Phase 1) - TGR-1202 Only [9 months]

      The highest dose of the study treatment that does not cause unacceptable side effects.

    2. Objective Response Rate (ORR) (Phase 2) [9 months]

      Defined as best response (complete response and partial response) by 4 cycles.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Target Population Phase I: Patients with relapsed or refractory NHL and HL Phase II:

    Patients with relapsed or refractory NHL

    Inclusion Criteria:
    • Phase I: Patients must have histologically confirmed R/R NHL or HL (defined by World Health Organization (WHO) criteria). Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are eligible. In addition, patients with NHL other than diffuse large B cell lymphomas (DLBCL) must have received at least 2 prior therapies. Patients with DLBCL and HL will be eligible if there is no available standard therapy.

    • Phase II: Patients must have histologically confirmed R/R NHL (as defined by WHO criteria). Patients with NHL other than diffuse large B cell lymphomas (DLBCL) must have received at least 2 prior therapies. Patients with DLBCL will be eligible if there is no available standard therapy.

    • Must have received front line chemotherapy. No upper limit for the number of prior therapies

    • Evaluable Disease in the Phase I, and measurable disease in the Phase II

    • Age > 18 years

    • Eastern Cooperative Oncology Group (ECOG) performance status < 2

    • Patients must have adequate organ and marrow function

    • Adequate Contraception

    • Ability to understand and the willingness to sign a written informed consent document

    Exclusion Criteria:
    1. Prior Therapy Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Systemic steroids that have not been stabilized (≥ 5 days) to the equivalent of ≤10 mg/day prednisone prior to the start of the study drugs. No other investigational agents are allowed.

    2. History of allergic reactions to TGR-1202 or carfilzomib

    3. Uncontrolled inter-current illness

    4. Pregnant women

    5. Nursing women

    6. Current malignancy or history of a prior malignancy

    7. Patient known to be Human Immunodeficiency Virus (HIV)-positive

    8. Active Hepatitis A, Hepatitis B, or Hepatitis C infection

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Columbia University Irving Medical Center - Center for Lymphoid MalignanciesNew YorkNew YorkUnited States10019

    Sponsors and Collaborators

    • Columbia University

    Investigators

    • Principal Investigator: Changchun Deng, MD, Assistant Professor of Clinical Medicine and Experimental Therapeutics

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Columbia University
    ClinicalTrials.gov Identifier:
    NCT02867618
    Other Study ID Numbers:
    • AAAP5661
    First Posted:
    Aug 16, 2016
    Last Update Posted:
    Jul 16, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail3 out of 14 subjects were enrolled (consented) but not accrued into study and did not receive study treatment.
    Arm/Group TitleCarfilzomib + TGR-1202
    Arm/Group DescriptionOral TGR-1202 will be given PO once daily on Days 1-28 and carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. Carfilzomib: Carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. This will be in combination with the oral TGR-1202 TGR-1202: Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib
    Period Title: Overall Study
    STARTED11
    COMPLETED11
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleCarfilzomib + TGR-1202
    Arm/Group DescriptionOral TGR-1202 will be given PO once daily on Days 1-28 and carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. Carfilzomib: Carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. This will be in combination with the oral TGR-1202 TGR-1202: Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib
    Overall Participants14
    Age, Customized (participants) [Number]
    18-21 years
    0
    0%
    22-29 years
    1
    7.1%
    30-39 years
    1
    7.1%
    40-49 years
    0
    0%
    50-59 years
    1
    7.1%
    60-69 years
    2
    14.3%
    70-79 years
    9
    64.3%
    80-89 years
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    6
    42.9%
    Male
    8
    57.1%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    14.3%
    Not Hispanic or Latino
    11
    78.6%
    Unknown or Not Reported
    1
    7.1%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    2
    14.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    3
    21.4%
    White
    8
    57.1%
    More than one race
    0
    0%
    Unknown or Not Reported
    1
    7.1%
    Region of Enrollment (participants) [Number]
    United States
    14
    100%

    Outcome Measures

    1. Primary Outcome
    TitleMaximum Tolerated Dose (MTD) (Phase 1) - TGR-1202 Only
    DescriptionThe highest dose of the study treatment that does not cause unacceptable side effects.
    Time Frame9 months

    Outcome Measure Data

    Analysis Population Description
    PI left the institution, study data was not complete or analyzed for Carfilzomib (Phase 2).
    Arm/Group TitleCarfilzomib + TGR-1202
    Arm/Group DescriptionOral TGR-1202 will be given PO once daily on Days 1-28 and carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. Carfilzomib: Carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. This will be in combination with the oral TGR-1202 TGR-1202: Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib
    Measure Participants11
    Number [mg]
    800
    2. Primary Outcome
    TitleObjective Response Rate (ORR) (Phase 2)
    DescriptionDefined as best response (complete response and partial response) by 4 cycles.
    Time Frame9 months

    Outcome Measure Data

    Analysis Population Description
    The data was not collected or analyzed due to PI leaving the institution.
    Arm/Group TitleCarfilzomib + TGR-1202
    Arm/Group DescriptionOral TGR-1202 will be given PO once daily on Days 1-28 and carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. Carfilzomib: Carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. This will be in combination with the oral TGR-1202 TGR-1202: Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib
    Measure Participants0

    Adverse Events

    Time FrameUp to 1 year post study treatment
    Adverse Event Reporting Description
    Arm/Group TitleCarfilzomib + TGR-1202
    Arm/Group DescriptionOral TGR-1202 will be given PO once daily on Days 1-28 and carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. Carfilzomib: Carfilzomib given intravenously twice a week for 3 consecutive weeks, on days 1, 2, 8, 9, 15, and 16 on the 28-day cycle. This will be in combination with the oral TGR-1202 TGR-1202: Oral TGR-1202 will be given PO once daily on Days 1-28 . This will be given in combination with the intravenous Carfilzomib
    All Cause Mortality
    Carfilzomib + TGR-1202
    Affected / at Risk (%)# Events
    Total1/11 (9.1%)
    Serious Adverse Events
    Carfilzomib + TGR-1202
    Affected / at Risk (%)# Events
    Total1/11 (9.1%)
    Blood and lymphatic system disorders
    Neutropenia1/11 (9.1%) 1
    Other (Not Including Serious) Adverse Events
    Carfilzomib + TGR-1202
    Affected / at Risk (%)# Events
    Total0/11 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleAna Ignat
    OrganizationColumbia University
    Phone212-305-3612
    Emailai2111@cumc.columbia.edu
    Responsible Party:
    Columbia University
    ClinicalTrials.gov Identifier:
    NCT02867618
    Other Study ID Numbers:
    • AAAP5661
    First Posted:
    Aug 16, 2016
    Last Update Posted:
    Jul 16, 2021
    Last Verified:
    Jun 1, 2021