Study of Pembrolizumab (MK-3475) in Combination With Romidepsin

• ClinicalTrials.gov Identifier: NCT03278782
• Recruitment Status: Recruiting
• First Posted: September 12, 2017
• Last Update Posted: July 17, 2019
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Study Description

Brief Summary:

This phase I/II trial studies the side effects of pembrolizumab and romidepsin and to see how well they work in treating participants with peripheral T-cell lymphoma that has come back or that does not respond to treatment. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Romidepsin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and romidepsin may work better than pembrolizumab alone in treating participants with recurrent or refractory peripheral T-cell lymphoma.

Condition or disease	Intervention/treatment	Phase
Recurrent Anaplastic Large Cell Lymphoma; Recurrent Angioimmunoblastic T-Cell Lymphoma; Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides; Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Anaplastic Large Cell Lymphoma; Refractory Angioimmunoblastic T-Cell Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma; Refractory Mycosis Fungoides; Refractory Peripheral T-Cell Lymphoma, Not Otherwise Specified; Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma	Biological: Pembrolizumab; Drug: Romidepsin	Phase 1; Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Evaluate the safety of pembrolizumab in combination with romidepsin. II. Estimate the response rate of the combination therapy in refractory or recurrent peripheral T-cell lymphoma (PTCL).

SECONDARY OBJECTIVES:

I. Estimate progression free survival (PFS). II. Estimate overall survival (OS). III. Estimate complete response (CR) and duration of response (DOR).

EXPLORATORY OBJECTIVES:

I. Assess activation of T-cells after treatment in peripheral blood and tumor microenvironment.

II. Correlate features of peripheral blood T-cell activation with toxicities, clinical response, and PFS.

OUTLINE:

Participants receive romidepsin intravenously (IV) over 4 hours on days 1 and 8 or day 8 of cycle 1 and days 1 and 8 of subsequent cycles and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days and then every 12 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 39 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Pembrolizumab (MK-3475) in Combination With Romidepsin in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma
• Actual Study Start Date: November 14, 2017
• Estimated Primary Completion Date: November 30, 2020
• Estimated Study Completion Date: November 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (romidepsin, pembrolizumab); Participants receive romidepsin IV over 4 hours on days 1 and 8 or day 8 of cycle 1 and days 1 and 8 of subsequent cycles and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 36 cycles in the absence of disease progression or unacceptable toxicity.	Biological: Pembrolizumab; Given IV; Other Names: Keytruda; Lambrolizumab; MK-3475; SCH 900475; Drug: Romidepsin; Given IV; Other Names: Antibiotic FR 901228; Depsipeptide; FK228; FR901228; Istodax; N-[(3S,4E)-3-Hydroxy-7-mercapto-1-oxo-4-heptenyl]-D-valyl-D-cysteinyl-(2Z)-2-amino-2-butenoyl-L-valine, (4->1) Lactone, Cyclic

Outcome Measures

Primary Outcome Measures :

1. Dose limiting toxicity (Phase I) [ Time Frame: Up to 21 days ]
   As determined by incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The phase I portion of the study follows standard 3+3 design. The 6 patients tested in the phase I at the dose finally determined as recommended phase II dose (RP2D) will be included in the response assessment of phase II study. Toxicity data will be summarized by type and severity for all patients who received the treatment regardless of the eligibility nor the duration or dose of the treatment received.
2. Overall response (OR) (Phase II) [ Time Frame: Up to 3 years ]
   As determined by Lugano Revised Response Criteria, International Society for Cutaneous Lymphomas (ISCL) for Research, and the European Organization for Research and Treatment of Cancer (EORTC) criteria. Response is defined by the best response during the therapy, as defined by the schedule of response evaluation. Summary statistics will be provided for continuous variables and categorical variables. The complete response (CR) and OR rates and their 95% confidence intervals will be reported. Fisher's exact test will be used to evaluate the association between two categorical variables. Wilcoxon rank sum test will be used to assess the difference in a continuous variable between patient groups.

Secondary Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: From the date of study registration and the date of progression, recurrence, or death without progression, whichever comes first, assessed up to 3 years ]
   Patients alive without progression are censored at the date they were last known to be without progression or recurrence and alive for PFS. Will be estimated using the method of Kaplan and Meier.
2. Overall survival [ Time Frame: From the date of study registration to the date of death from any cause, assessed up to 3 years ]
   Will be estimated using the method of Kaplan and Meier.
3. Complete response [ Time Frame: Up to 3 years ]
   As determined by Lugano Revised Response Criteria, ISCL for Research and the EORTC criteria. Response is defined by the best response during the therapy, as defined by the schedule of response evaluation. Summary statistics will be provided for continuous variables and categorical variables. The CR and OR rates and their 95% confidence intervals will be reported. Fisher's exact test will be used to evaluate the association between two categorical variables. Wilcoxon rank sum test will be used to assess the difference in a continuous variable between patient groups.
4. Duration of response [ Time Frame: Up to 3 years ]
   As determined by Lugano Revised Response Criteria, ISCL for Research, and the EORTC criteria. Response is defined by the best response during the therapy, as defined by the schedule of response evaluation. Summary statistics will be provided for continuous variables and categorical variables Fisher's exact test will be used to evaluate the association between two categorical variables. Wilcoxon rank sum test will be used to assess the difference in a continuous variable between patient groups. Will be estimated using the method of Kaplan and Meier.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients with peripheral T-cell lymphoma (including but not limited to peripheral T-cell lymphoma, not otherwise specified [PTCL-NOS], angioimmunoblastic T-cell lymphoma, anaplastic large T-cell lymphoma). Patients with mycosis fungoides with large cell transformation with measurable disease is eligible.
• Disease status defined as refractory to or relapsed after >=1 prior treatment lines.
• Subjects with ALK+, anaplastic large cell lymphoma (ALCL) should have been treated with, be ineligible for, or have refuse chemotherapy and brentuximab prior to enrollment on the current study.
• Patients with a measurable disease, defined by a node or mass with the longest diameter >= 1.5 cm.
• Be willing and able to provide written informed consent/assent for the trial.
• Patients with PTCL should have radiographically measurable disease >= 1.5 cm.
• Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen.
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale.
• Absolute neutrophil count (ANC) >= 1,500 /mcL.
• Platelets >= 100,000 / mcL.
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment).

• Serum creatinine OR measured or calculated creatinine clearance glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl) =< 1.5 x upper limit of normal (ULN) OR =< 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN.

  • Creatinine clearance should be calculated per institutional standard.
• Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN.
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases.
• Albumin >= 2.5 mg/dL.
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants.
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• Thromboplastin time (aPTT)anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
• Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency, is receiving systemic steroids above physiologic dose (> 10 mg/day prednisone or equivalent) within 7 days of start of therapy or is receiving any other form of immunosuppressive therapy.
• Has a known history of active TB (Bacillus tuberculosis).
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has known history of non-infectious pneumonitis that required systemic steroid use, or has active pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
• Has known active hepatitis B (e.g., hepatitis b surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected).
• Baseline electrocardiogram (EKG) shows corrected QT interval by Fridericia (QTcF) > 470 msec.
• Concomitant use of strong CYP3A4 inhibitors and inducers.
• Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.
• Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of graft versus host disease (GVHD).

Contacts and Locations

Contacts

Contact: Swaminathan P. Iyer, MD; 713-792-2860; spiyer@mdanderson.org

Locations

United States, Texas

M D Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Swaminathan P. Iyer 713-792-2860

Principal Investigator: Swaminathan P. Iyer

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Michelle A Fanale; M.D. Anderson Cancer Center

More Information

Additional Information:

The University of Texas (UT) MD Anderson Cancer Center Official Website 

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT03278782 History of Changes
• Other Study ID Numbers: 2017-0272; NCI-2018-01051 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2017-0272 ( Other Identifier: M D Anderson Cancer Center ); P30CA016672 ( U.S. NIH Grant/Contract )
• First Posted: September 12, 2017
• Last Update Posted: July 17, 2019
• Last Verified: July 2019

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

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Lymphoma, T-Cell, Cutaneous; Lymphoma, Large-Cell, Anaplastic; Lymphoma, T-Cell, Peripheral; Mycoses; Mycosis Fungoides; Immunoblastic Lymphadenopathy; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphadenopathy; Pembrolizumab; Romidepsin; Antineoplastic Agents, Immunological; Antineoplastic Agents; Antibiotics, Antineoplastic