Clinical Trials /

Durvalumab in Different Combinations With Pralatrexate, Romidepsin and Oral 5-Azacitidine for Lymphoma

NCT03161223

Description:

This is an open-label, Phase 1/2a, dose-finding study with an initial phase 1 portion, articulated in four separate treatment arms, followed by a dedicated phase 2 for qualifying treatment Arm(s). The primary objective of the Phase 1 portion is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of: Durvalumab, oral 5-azacitidine, and romidepsin (Arm A); durvalumab, pralatrexate, and romidepsin (Arm B); durvalumab and romidepsin (Arm C); or durvalumab and oral 5-azacitidine (Arm D), in patients with peripheral T-cell lymphoma (PTCL). The safety and toxicity profile of these combinations will be evaluated throughout the entire study. If one or more of the combinations in Arms A, B, C, or D are found to be feasible and an MTD is established, the phase 2 portion of the study will be initiated for the combination(s) with the strongest efficacy signal provided acceptable toxicity.

Related Conditions:
  • Peripheral T-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab in Different Combinations With Pralatrexate, Romidepsin and Oral 5-Azacitidine for Lymphoma
  • Official Title: Phase 1/2a Study of Anti-PD-L1 Monoclonal Antibody Durvalumab in Combination With Pralatrexate and Romidepsin, Oral 5-Aza and Romidepsin, Romidepsin Alone, or Oral 5-Azacitidine for Treatment of Patients With Relapsed and Refractory PTCL

Clinical Trial IDs

  • ORG STUDY ID: AAAR0365
  • NCT ID: NCT03161223

Conditions

  • Lymphoma, T-Cell

Interventions

DrugSynonymsArms
DurvalumabMEDI4736A: Oral 5-azacitidine, durvalumab, romidepsin
PralatrexateFolotynB: durvalumab, pralatrexate, romidepsin
RomidepsinDepsipeptideA: Oral 5-azacitidine, durvalumab, romidepsin
5-AzacitidineVidaza, Oral 5-AzacitidineA: Oral 5-azacitidine, durvalumab, romidepsin

Purpose

This is an open-label, Phase 1/2a, dose-finding study with an initial phase 1 portion, articulated in four separate treatment arms, followed by a dedicated phase 2 for qualifying treatment Arm(s). The primary objective of the Phase 1 portion is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of: Durvalumab, oral 5-azacitidine, and romidepsin (Arm A); durvalumab, pralatrexate, and romidepsin (Arm B); durvalumab and romidepsin (Arm C); or durvalumab and oral 5-azacitidine (Arm D), in patients with peripheral T-cell lymphoma (PTCL). The safety and toxicity profile of these combinations will be evaluated throughout the entire study. If one or more of the combinations in Arms A, B, C, or D are found to be feasible and an MTD is established, the phase 2 portion of the study will be initiated for the combination(s) with the strongest efficacy signal provided acceptable toxicity.

Detailed Description

      The peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphoid
      neoplasms and account for 10-15% of all newly diagnosed cases of non-Hodgkin's lymphoma
      (NHL). The current prevalence of PTCL in the United States is estimated to be approximately
      9,500 patient. Treatment options for patients with relapsed/refractory (R/R) PTCL have been
      limited. This study focuses on exploring rational combinations of these T-cell active agents
      in an effort to develop novel treatment platforms.
    

Trial Arms

NameTypeDescriptionInterventions
A: Oral 5-azacitidine, durvalumab, romidepsinOtherArm A: Patients will first undergo a 7-day lead-in phase of 5-azacitidine. 5-azacitidine will be administered orally from day 1 to day 14 (including the lead-in phase), durvalumab will be administered intravenously on day 8 and romidepsin intravenously on days 8 and 15 of a 28-day treatment cycle
  • Durvalumab
  • Romidepsin
  • 5-Azacitidine
B: durvalumab, pralatrexate, romidepsinOtherArm B: Durvalumab will be administered intravenously on day 1, pralatrexate will be administered intravenously on days 1 and 15, and romidepsin will be administered intravenously on days 1 and 15. Each treatment cycle will last 28 days. All patients receiving pralatrexate will receive folic acid and vitamin B12 supplementation according to the drug package insert. Leucovorin rescue is also allowed at the dose of 15 mg orally twice daily on days 3 to 6 and 17 to 20.
  • Durvalumab
  • Pralatrexate
  • Romidepsin
C: durvalumab, romidepsinOtherArm C: Durvalumab will be administered intravenously on day 1 and romidepsin will be administered intravenously on days 1, 8, and 15 of a 28-day treatment cycle
  • Durvalumab
  • Romidepsin
D: durvalumab, 5-azacitidineOtherArm D: Patients will first undergo a 7-day lead-in phase of 5-azacitidine. 5-azacitidine will be administered orally from day 1 to day 14 (including the lead-in phase) and durvalumab will be administered intravenously on day 8 of a 28-day treatment cycle
  • Durvalumab
  • 5-Azacitidine

Eligibility Criteria

        Inclusion Criteria (these criteria apply to both the phase 1 and phase 2 portion of the
        study)

          -  Age >18 years at the time of signing the informed consent

          -  Patients must have histologically confirmed newly diagnosed (ND) or
             Relapsed/Refractory Peripheral T-Cell Lymphoma (R/R PTCL) defined according to the
             2016 World Health Organization (WHO) classification criteria.

          -  Patients with R/R PTCL who have received at least one previous line of therapy are
             eligible to be enrolled in this study.

          -  Patients who are candidate for an autologous or allogeneic stem cell transplantation
             (SCT) will be allowed to receive the study drugs as a "bridge" to transplantation.

          -  Evaluable (phase 1) or measurable (phase 2) disease.

          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

          -  Patients must have adequate organ and marrow function as defined by:

               1. Aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤ 2 x
                  institutional upper limit of normal (ULN); total bilirubin ≤ 1.5 x ULN (AST, ALT,
                  and total bilirubin ≤ 3 × ULN in subjects with documented Gilbert's syndrome or
                  hyperbilirubinemia clearly attributed to lymphoma involvement of the liver);

               2. Creatinine levels < 2 mg/dL; or creatinine clearance > 40 mL/min

               3. Absolute neutrophil count (ANC) > 1,000/μL; platelet count > 75,000/μL

               4. Negative urine or serum pregnancy test for women of childbearing potential. All
                  women of childbearing potential must agree to use an effective barrier method of
                  contraception (either an intrauterine device (IUD) or double barrier method using
                  condoms or a diaphragm plus spermicide) during the treatment period and for at
                  least 1 month after discontinuation of the study drugs. Male subjects should use
                  effective barrier method of contraception during the treatment period and for at
                  least 3 months after discontinuation of the study drugs.

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

          -  Ability to adhere to the study visit schedule and other protocol requirements

        Exclusion Criteria (these criteria apply to both the phase 1 and phase 2 portion of the
        study)

          -  Prior Therapy (for patients with R/R PTCL)

               1. Exposure to any agent targeting PD-1, PD-L1 or cytotoxic T-lymphocyte-associated
                  protein 4 (CTLA-4).

               2. For three-drug combinations, the patient must not have been exposed to at least
                  two of those drugs. For two drugs combinations patients must not have been
                  exposed to any of those drugs. Patients will be enrolled in the first treatment
                  Arm that satisfies this exclusion criterion, according to the following sequence:
                  Arm A; Arm B; Arm C; Arm D.

               3. Exposure to biologic therapy, immunotherapy, chemotherapy, investigational agent
                  for malignancy, or radiation therapy within 2 weeks prior to entering the study
                  or lack of resolution of AE due to previously administered antineoplastic therapy
                  to grade 1 or less according to National Cancer Institute (NCI) Common
                  Terminology Criteria for Adverse Events (CTCAE), Version 4.0.

               4. Current or prior use of immunosuppressive medication within 14 days prior to
                  first dose of durvalumab. The following are exceptions to this criterion:
                  intranasal, inhaled, topical or local steroid injections (e.g., intra-articular
                  injection); steroids as premedication for hypersensitivity reactions; systemic
                  corticosteroid at physiologic doses not to exceed 10 mg/day of prednisone or
                  equivalent for at least 5 days prior to the start of the study drugs.

               5. Prior allogeneic SCT

          -  History of, or suspected allergic reactions to, durvalumab, pralatrexate, oral
             5-azacitidine, or romidepsin or any of their excipients.

          -  For patients who are treated with oral 5-azacitidine, any gastrointestinal disorder
             that would interfere with the absorption of the study drug

          -  Concomitant use of CYP3A4 inhibitors

          -  Uncontrolled intercurrent illness.

          -  Any of the following cardiac abnormalities (only for patients receiving romidepsin):

               1. Congenital long QT syndrome;

               2. corrected QT (QTc) interval ≥ 501 milliseconds;

               3. Patients taking drugs leading to significant QT prolongation (See Appendix 3);

               4. Myocardial infarction within 6 months of cycle 1, day 1. [Subjects with a history
                  of myocardial infarction between 6 and 12 months prior to cycle 1, day 1, who are
                  asymptomatic and have had a negative cardiac risk assessment (treadmill stress
                  test, nuclear medicine stress test, or stress echocardiogram) since the event,
                  may participate];

               5. Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV)
                  block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50
                  beats/min);

               6. Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV In
                  any patient in whom there is doubt, the patient should have a stress imaging
                  study and, if abnormal, angiography to define whether or not CAD is present;

               7. An ECG recorded at screening showing evidence of cardiac ischemia (ST depression
                  of ≥ 2 mm, measured from isoelectric line to the ST segment). If in any doubt,
                  the patient should have a stress imaging study and, if abnormal, angiography to
                  define whether or not CAD is present;

               8. Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class
                  II to IV definitions (see Appendix 5) and/or ejection fraction < 40% by
                  multitargeted acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic
                  resonance imaging (MRI);

               9. A known history of sustained ventricular tachycardia (VT), ventricular
                  fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently
                  addressed with an automatic implantable cardioverter defibrillator (AICD);

              10. Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
                  other causes;

              11. Uncontrolled hypertension, i.e., blood pressure (BP) of ≥ 160/95; patients who
                  have a history of hypertension controlled by medication must be on a stable dose
                  (for at least one month) and meet all other inclusion criteria; or

              12. Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
                  doses of beta-blockers).

          -  Pregnancy or breast-feeding.

          -  Active concurrent malignancy (except non-melanoma skin cancer, prostatic
             intraepithelial neoplasia, or carcinoma in situ of the cervix). Patients whose
             lymphoma has transformed from a less aggressive histology remain eligible.

          -  Receipt of solid organ transplant.

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis with the
             exception of a prior episode that has resolved or diverticulosis, celiac disease,
             irritable bowel disease, or other serious gastrointestinal chronic conditions
             associated with diarrhea; systemic lupus erythematosus; Wegener's syndrome
             [granulomatosis with polyangiitis]; myasthenia gravis; Graves' disease; rheumatoid
             arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of
             treatment. The following are exceptions to this criterion: subjects with vitiligo or
             alopecia; subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on
             hormone replacement; or subjects with psoriasis not requiring systemic treatment.

          -  Central nervous system (CNS) involvement, including lymphomatous meningitis.

          -  Known active hepatitis A, B or C virus infection.

          -  Known HIV infection.

          -  History of primary immunodeficiency.

          -  Receipt of live, attenuated vaccine within 30 days prior to study entry. Enrolled
             patients should not receive live vaccine during the study and 30 days after the last
             dose of durvalumab.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:1 year
Safety Issue:
Description:The highest dose of study treatment that does not cause unacceptable side effects in patients with R/R PTCL in each study arm

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:1 year
Safety Issue:
Description:ORR will be defined as the sum of complete response rate and partial response rate based on evaluation of best response in each patient.
Measure:Duration of Response (DoR)
Time Frame:1 year
Safety Issue:
Description:Time from documentation of tumor response to disease progression
Measure:Progression Free Survival (PFS)
Time Frame:1 year
Safety Issue:
Description:Time from study treatment until disease progression or death

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Columbia University

Trial Keywords

  • Durvalumab
  • Pralatrexate
  • Romidepsin
  • 5-Azacitidine

Last Updated

January 22, 2020