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

NCT03161223 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: AAAR0365
• Study Type: interventional
• Target: 148
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Lymphoma, T-Cell

Keywords

Durvalumab; Pralatrexate; Romidepsin; 5-Azacitidine

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD)

  The highest dose of study treatment that does not cause unacceptable side effects in patients with R/R PTCL in each study arm

  1 year

Secondary Outcomes (3)

• Overall Response Rate (ORR)

  1 year

• Duration of Response (DoR)

  1 year

• Progression Free Survival (PFS)

  1 year

Study Arms (4)

A: Oral 5-azacitidine, durvalumab, romidepsin

OTHER

Arm 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

Drug: Durvalumab; Drug: Romidepsin; Drug: 5-Azacitidine

B: durvalumab, pralatrexate, romidepsin

OTHER

Arm 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.

Drug: Durvalumab; Drug: Pralatrexate; Drug: Romidepsin

C: durvalumab, romidepsin

OTHER

Arm 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

Drug: Durvalumab; Drug: Romidepsin

D: durvalumab, 5-azacitidine

OTHER

Arm 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

Drug: Durvalumab; Drug: 5-Azacitidine

Interventions

Durvalumab DRUG

Durvalumab is an investigational human monoclonal antibody that works to inhibit (block) a protein called programmed cell death-1 ligand 1 (PD-L1). Durvalumab has not been approved by the FDA for the treatment of PTCL but has been given to patients other types of cancers. Given intravenously (through the vein). Starting dose: 1500 mg

Also known as: MEDI4736

A: Oral 5-azacitidine, durvalumab, romidepsin; B: durvalumab, pralatrexate, romidepsin; C: durvalumab, romidepsin; D: durvalumab, 5-azacitidine

Pralatrexate DRUG

Pralatrexate is an antimetabolite drug. Pralatrexate alone is FDA-approved for the treatment of PTCL. Given intravenously (through the vein). Starting dose: 25 mg/m2

Also known as: Folotyn

B: durvalumab, pralatrexate, romidepsin

Romidepsin DRUG

Romidepsin is another type of chemotherapy known as histone deacetylase (HDAC) inhibitors. Romidepsin has not been approved for use in lymphoma other than Cutaneous T cell lymphoma (CTCL) by the FDA. Given intravenously (through the vein). Starting dose: 12 mg/m2

Also known as: Depsipeptide

A: Oral 5-azacitidine, durvalumab, romidepsin; B: durvalumab, pralatrexate, romidepsin; C: durvalumab, romidepsin

5-Azacitidine DRUG

Oral 5-azacitidine is used for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Azacitidine prevents the body from making DNA and RNA that cells need to grow. This stops the growth of cancer cells and causes them to die. Given by mouth (orally). Starting dose: 300 mg daily

Also known as: Vidaza, Oral 5-Azacitidine

A: Oral 5-azacitidine, durvalumab, romidepsin; D: durvalumab, 5-azacitidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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);
• Creatinine levels \< 2 mg/dL; or creatinine clearance \> 40 mL/min
• Absolute neutrophil count (ANC) \> 1,000/μL; platelet count \> 75,000/μL
• 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

You may not qualify if:

• Prior Therapy (for patients with R/R PTCL)
• Exposure to any agent targeting PD-1, PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
• 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.
• 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.
• 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):
• Congenital long QT syndrome;
• corrected QT (QTc) interval ≥ 501 milliseconds;
• Patients taking drugs leading to significant QT prolongation (See Appendix 3);
• Myocardial infarction within 6 months of cycle 1, day 1. \[Subjects with a history of myocardial infarction between 6 and 12 months prior to cycle 1, day 1, who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event, may participate\];
• 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);

Sponsors & Collaborators

• University of Virginia: lead

Study Sites (1)

University of Virginia

Charlottesville, Virginia, 22903, United States

RECRUITING

MeSH Terms

Conditions

Lymphoma, T-Cell

Interventions

durvalumab; 10-propargyl-10-deazaaminopterin; romidepsin; Depsipeptides; Azacitidine

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Enrica Marchi, M.D., PhD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Abdelmalek Marian

CONTACT

434-924-5834; mka6s@hscmail.mcc.virginia.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase 1 A minimum of 3 patients will be treated at the entry Dose Level, that is the MTD, in each arm. An estimated 10 patients will be accrued in each Arm, assuming ≤ 1 patients experience DLT. If a DLT is reached early we will treat fewer patients. For each study Arm, we will expand the MTD cohort to a total of 10 patients. We estimate that a total of 40 patients will be needed. Phase 2 Once the recommended phase 2 dose is identified, a planning meeting with the Sponsor and involved investigators will be convened to discuss which Arm(s) to advance to phase 2. The sample size of the phase 2 portion of the study will be calculated on an optimal 2-stage design. We will first enroll 8 patients. If at least 3 objective responses (PR or CR) are seen, then an additional 16 patients will be enrolled. If 10 or fewer patients respond, the combination will not be considered for further study. We will enroll a total of 24 patients per arm.

Study Record Dates

• First Submitted: May 18, 2017
• First Posted: May 19, 2017
• Study Start: May 30, 2018
• Primary Completion: February 1, 2023
• Study Completion: February 1, 2023
• Last Updated: March 31, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)