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Durvalumab, Pralatrexate, Romidepsin, and Oral Azacitidine in Treating Patients with Peripheral T-Cell Lymphoma

Trial Status: Active

This phase I / IIa trial studies the side effects and best dose of durvalumab, pralatrexate, romidepsin, and oral azacitidine, and to see how well they work in treating patients with peripheral T-cell lymphoma. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Pralatrexate is a chemotherapy drug that blocks how cells are made and therefore the growth of cancer cells can be slowed, stopped, or decreased. Romidepsin is another type of chemotherapy known as HDAC (histone deacetylase) inhibitors, which blocks the function of enzymes that help remove the acetyl groups from various proteins in cells. HDAC inhibitors help stop the growth of cancer cells and can help kill the cancer cells. Oral azacitidine prevents the body from making deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) that cells need to grow, which stops the growth of cancer cells and causes them to die. It is not yet known which combination of these drugs work best in treating patients with peripheral T-cell lymphoma.

Inclusion Criteria

  • Patients must have histologically confirmed PTCL defined according to the 2016 World Health Organization (WHO) classification criteria
  • Patients with previously untreated disease, relapsed or refractory disease are allowed irrespective of the number of lines of prior therapy
  • Patients who are candidate for an autologous or allogeneic stem cell transplantation (SCT) are eligible
  • Evaluable (phase 1) or measurable (phase 2) disease
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Aspartate aminotransferase (aspartate transaminase [AST]) and alanine aminotransferase (alanine transaminase [ALT]) levels =< 2 x institutional upper limit of normal (ULN) (AST, ALT, and total bilirubin =< 3 x ULN in subjects with documented Gilbert’s syndrome or hyperbilirubinemia clearly attributed to lymphoma involvement of the liver)
  • Total bilirubin =< 1.5 x ULN (AST, ALT, and total bilirubin =< 3 x 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/uL
  • Platelet count > 75,000/uL
  • 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 3 months 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

  • Prior Therapy (for patients with R/R PTCL): * Exposure to any agent targeting PD-L1 * Patients must fulfill the following criteria regarding prior exposure to study drugs: in Arm A (azacitidine, romidepsin, durvalumab) no prior exposure to durvalumab, and no prior exposure to azacitidine (irrespectively to formulation) or romidepsin; in Arm B (pralatrexate, romidepsin, durvalumab) no prior exposure to durvalumab, and no prior exposure to pralatrexate or romidepsin; in Arm C (romidepsin, durvalumab) no prior exposure to durvalumab, and no prior exposure to romidepsin; in Arm D (5-oral azacytidine and durvalumab) no prior exposure to durvalumab and no prior exposure to azacitidine irrespectively of formulation * Lack of resolution of adverse events (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; * 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 electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min); * 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; * 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; * Congestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or ejection fraction < 40% by multitargeted acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI); * 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); * Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes; * 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 * 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 [e.g., 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; patients with autoimmune phenomena secondary to active lymphoma (e.g. autoimmune hemolytic anemia)
  • Central nervous system (CNS) involvement, including lymphomatous meningitis
  • Known active hepatitis A, B or C virus infection
  • Known human immunodeficiency virus (HIV) infection
  • History of primary immunodeficiency
  • Administration 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

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: Enrica Marchi
Phone: 212-326-5720

Italy

Bologna
Universita Di Bologna
Status: APPROVED
Contact: Pier Luigi Zinzani

Korea, Republic of

Seoul
Samsung Medical Center
Status: APPROVED
Contact: Seok Won Kim

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination of durvalumab, oral azacitidine (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 newly diagnosed (ND) or relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL). (Phase I)

II. Evaluate the safety and toxicity of the combination 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 ND or R/R PTCL. (Phase I)

III. Describe the overall response rate (ORR) (that is, the sum of complete response rate and partial response rate) after treatment with the combination 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 ND or R/R PTCL. (Phase II)

SECONDARY OBJECTIVES:

I. Describe the maximum number of cycles received. (Phase I)

II. Describe the number of dose delays and dose reductions at the MTD. (Phase I)

III. Describe the anti-tumor activity of the combinations in Arm A, Arm B, Arm C, and Arm D. (Phase I)

IV. Evaluate the overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR) of patients in each study arm (Phase I).

V. Establish the pharmacokinetic (PK) profile for the combinations in Arm A, Arm B, Arm C, and Arm D during cycle 1 at various time intervals. (Phase I)

VI. Estimate the DOR and PFS after treatment with the combinations in Arm A, Arm B, Arm C, or Arm D. (Phase II)

VII. Estimate the overall survival (OS) of patients on study. (Phase II)

EXPLORATORY OBJECTIVES:

I. Evaluate pharmacodynamic markers of drug effect in serial peripheral blood samples and paired tumor tissue biopsies (before and after treatment). (Phase I)

II. Evaluate pharmacodynamic markers of drug effect in paired tissue biopsies (before and after treatment). (Phase II)

III. Correlate biomarkers of drug effect with response to therapy. (Phase II)

IV. Evaluate the response to, and outcome after subsequent treatments, where applicable. (Phase II)

OUTLINE: Patients are assigned to 1 of 4 arms.

ARM A: Patients receive oral azacitidine orally (PO) on days 1-14 of cycle 1 and on days 7-14 of subsequent cycles, romidepsin intravenously (IV) over 4 hours on days 8 and 15, and durvalumab IV over 60 minutes on day 8. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive romidepsin IV over 4 hours, pralatrexate IV over 3-5 minutes on days 1 and 15, and durvalumab IV over 60 minutes on day 1. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive romidepsin IV over 4 hours on days 1, 8, and 15, and durvalumab IV over 60 minutes on day 1. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM D: Patients receive oral azacitidine PO as in Arm A and durvalumab IV as in Arm A. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then every 3 months for 1 year.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center

Principal Investigator
Enrica Marchi

  • Primary ID AAAR0365
  • Secondary IDs NCI-2018-00458
  • Clinicaltrials.gov ID NCT03161223