Nivolumab With Standard of Care Chemotherapy for Peripheral T Cell Lymphomas

Nivolumab With Standard of Care Chemotherapy for the First Line Treatment of Peripheral T Cell Lymphoma

This regimen aims to become the first line treatment for peripheral T cell lymphoma, using nivolumab with the standard of care chemotherapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Peripheral T Cell Lymphoma
• Intervention / Treatment: Drug: Nivolumab; Drug: Etoposide; Drug: Prednisolone; Drug: Oncovin; Drug: Cyclophosphamide; Drug: Hydroxydaunorubicin

Detailed Description

Patients in this study will receive nivolumab in combination with the standard of care dose-adjusted EPOCH (etoposide, prednisone, vincristine, doxorubicin, cyclophosphamide) for six 21 day cycles. Patients will then have an autologous stem cell transplant or continue to receive maintenance therapy with nivolumab.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Ability to sign and date the consent form.
2. Stated willingness to comply with all study procedures and be available for the duration of the study.
3. Be a male or female aged 18-80.
4. Histologically confirmed new diagnosis of Stage II, III or IV Peripheral T-cell Non-Hodgkin's lymphoma not otherwise specified (NOS), Anaplastic large cell lymphoma (ALK-negative) (ALK-positive if IPI 3, 4, or 5), Angioimmunoblastic T-cell lymphoma, Enteropathy associated T-cell lymphoma (MEITL and EATL), Hepatosplenic T-cell lymphoma, y/8 T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma, and Nodal T-cell lymphomas with T-follicular helper phenotype.
5. Available pathology material (fine needle aspirate is inadequate) for review at the University of Colorado.
6. No prior therapy with the exception of prior radiation therapy and/or 1 cycle of chemotherapy (may be any chemotherapy regimen or even prednisone alone) based on current diagnosis and clinical condition. If given cytotoxic chemotherapy (one cycle only, e.g. CHOP), this cycle of treatment will count toward the 6 cycles of treatment given in the study.
7. ECOG performance status 0 - 2.

8. Laboratory status as follows:

   • ANC > 1000 cells/mm3, unless cytopenias due to lymphoma (i.e., bone marrow involvement or splenomegaly)
   • Platelet Count > 100,000 /μL, or > 50,000 /μL if bone marrow involvement or splenomegaly
   • Total bilirubin ≤1.5 x upper normal limit, or ≤ 3 x upper normal limit if documented hepatic involvement with lymphoma, or ≤ 5 x upper normal limit if history of Gilbert's Disease.
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit (≤ 5 x upper normal limit if documented hepatic involvement with lymphoma).
   • Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) > 45 mL/min (Cockcroft-Gault, Appendix)
   • PT or INR, and PTT ≤ 1.5 x upper limit of normal unless patient is receiving anticoagulants. If patient is on warfarin therapy, levels should be within therapeutic range.
9. Patients with measurable disease. Measurable disease is defined as having at least one objective measurable disease parameter. A clearly defined, bi-dimensionally measurable defect or mass measuring at least 1.5 cm in diameter on the CT portion of a PET/CT or CT scan or MRI (if appropriate) will constitute measurable disease. Proof of lymphoma in the liver is required by a confirmation biopsy unless there is measurable disease by imaging. Skin lesions can be used as measurable disease provided bi-dimensional measurements are possible. Patients with non-measurable but evaluable disease may be eligible after discussion with the PI. Abnormal PET/CT scans will not constitute evaluable disease, unless verified by the CT scan portion, CT scan, or other appropriate imaging.
10. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 180 days after the last study treatment. A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
11. Patient must be able to adhere to the study visit schedule and other protocol requirements.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. An additional malignancy treated with palliative intent within the past 2 years. Malignancies in patients who have completed definitive treatment with curative intent >1 year will be permitted after discussion with the PI. Adequately treated basal cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason Grade 6 or less with stable PSA levels are allowed.
2. Patients with a diagnosis of other PTCL histologies other than those specified in the inclusion criteria.
3. Primary T-cell CNS lymphoma; however, secondary CNS disease is not an exclusion criteria.
4. Pregnant or breastfeeding females.
5. Contraindication to any of the required concomitant drugs or supportive treatments.
6. Any other clinically significant medical disease or condition laboratory abnormality or psychiatric illness that, in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
7. Ejection fraction of <45% by either MUGA or ECHO.
8. Has immunodeficiency or is being treated with immuno-suppressive therapy (aside from medications used to treat lymphoma) within 7 days of first dose of study treatment. Inhaled or topical steroids are accepted. Prednisone used to treat adrenal insufficiency in the absence of auto-immune disease is also acceptable.
9. Auto-immune condition requiring immuno-suppressive disease modifying therapy within the prior 2 years. Replacement therapy, e.g. levothyroxine for thyroiditis or insulin for diabetes are acceptable.
10. History of non-infectious pneumonitis requiring immuno-suppressive therapy.
11. Active hepatitis B or C (with measurable virus or antigen in serum) or HIV. Patients who are seropositive because of hepatitis B virus vaccine or have a history of hepatitis B (with no measurable virus or antigen in serum) are eligible.
12. Prior PD-1 or PD-L1 antibody treatment.
13. Has received a live virus vaccine in 30 days preceding start of therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Nivolumab and EPOCH; Patients will all receive nivolumab in combination with standard dose adjusted EPOCH for a planned 6 cycles, unless treatment is stopped early for disease progression or toxicity. Patients that have already received up to 1 cycle of standard of care chemotherapy will receive 5 cycles of experimental nivolumab + DA-EPOCH (dose adjusted, continuous infusion etoposide, prednisone, vincristine, doxorubicin, and bolus dosing of cyclophosphamide) for a total of 6 cycles of chemotherapy.

Drug: Nivolumab; Nivolumab injection is to be administered as an IV infusion.; Other Names: Opdivo; Drug: Etoposide; Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a >10% weight gain or loss. Patients receive six 21-day cycles of the medications.; Other Names: Toposar; Vepesid; Drug: Prednisolone; Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a >10% weight gain or loss. Patients receive six 21-day cycles of the medications.; Other Names: Millipred; Oraped; PediaPred; Drug: Oncovin; Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a >10% weight gain or loss. Patients receive six 21-day cycles of the medications.; Other Names: Leurocristine; Vincristine; Drug: Cyclophosphamide; Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a >10% weight gain or loss. Patients receive six 21-day cycles of the medications.; Other Names: cytophosphane; Drug: Hydroxydaunorubicin; Dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using the Mosteller formula and administered through IV. Dose adjustments at the beginning of each cycle do not need to be made unless there has been a >10% weight gain or loss. Patients receive six 21-day cycles of the medications.; Other Names: Adriamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Toxicity analysis of nivolumab will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 and relationship to study drug or the amount of grade 4-5 non-hematologic toxicities.	Start of study to end of study, for up to four years
Efficacy: Overall Response Rate	Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy.	Start of study to end of study, for up to four years
Efficacy: Complete Response Rate	Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy.	Start of study to end of study, for up to four years
Efficacy: Partial Response Rate	Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy.	Start of study to end of study, for up to four years
Efficacy: Rate of Stable Disease	Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy.	Start of study to end of study, for up to four years
Efficacy: Rate of Progressive Disease	Efficacy will be measured according to 2017 RECIL criteria. Responses will be assessed by the investigator and will be based on PET/CT scan to be obtained after 6 cycles of induction chemotherapy.	Start of study to end of study, for up to four years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS will be descriptive in nature (no formal statistical analyses will be conducted).	Start of study to end of study, for up to four years
Correlative Analysis: Determine immune-related predictors of response to nivolumab plus EPOCH chemotherapy	This will be descriptive in nature (no formal statistical analyses will be conducted).	Start of study to end of study, for up to four years

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Brad Haverkos, MD, University of Colorado, Denver

Publications and helpful links

General Publications

• Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008 Sep 1;26(25):4124-30. doi: 10.1200/JCO.2008.16.4558. Epub 2008 Jul 14.
• Ellin F, Landstrom J, Jerkeman M, Relander T. Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood. 2014 Sep 4;124(10):1570-7. doi: 10.1182/blood-2014-04-573089. Epub 2014 Jul 8.
• Maeda Y, Nishimori H, Yoshida I, Hiramatsu Y, Uno M, Masaki Y, Sunami K, Masunari T, Nawa Y, Yamane H, Gomyo H, Takahashi T, Yano T, Matsuo K, Ohshima K, Nakamura S, Yoshino T, Tanimoto M. Dose-adjusted EPOCH chemotherapy for untreated peripheral T-cell lymphomas: a multicenter phase II trial of West-JHOG PTCL0707. Haematologica. 2017 Dec;102(12):2097-2103. doi: 10.3324/haematol.2017.167742. Epub 2017 Sep 29.
• Schmitz N, Trumper L, Ziepert M, Nickelsen M, Ho AD, Metzner B, Peter N, Loeffler M, Rosenwald A, Pfreundschuh M. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010 Nov 4;116(18):3418-25. doi: 10.1182/blood-2010-02-270785. Epub 2010 Jul 21.
• Dunleavy K, Pittaluga S, Shovlin M, Roschewski M, Lai C, Steinberg SM, Jaffe ES, Wilson WH. Phase II trial of dose-adjusted EPOCH in untreated systemic anaplastic large cell lymphoma. Haematologica. 2016 Jan;101(1):e27-9. doi: 10.3324/haematol.2015.131151. Epub 2015 Oct 30. No abstract available.
• Ghafouri S, Fenerty K, Schiller G, de Vos S, Eradat H, Timmerman J, Larson S, Mead M. Real-World Experience of Axicabtagene Ciloleucel and Tisagenlecleucel for Relapsed or Refractory Aggressive B-cell Lymphomas: A Single-Institution Experience. Clin Lymphoma Myeloma Leuk. 2021 Dec;21(12):861-872. doi: 10.1016/j.clml.2021.07.002. Epub 2021 Jul 19.

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2018
• Primary Completion (Actual): September 20, 2022
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 29, 2018
• First Submitted That Met QC Criteria: July 12, 2018
• First Posted (Actual): July 16, 2018

Study Record Updates

• Last Update Posted (Actual): September 5, 2023
• Last Update Submitted That Met QC Criteria: August 31, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Nivolumab; Standard of Care; EPOCH; First Line Treatment
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Prednisolone; Prednisolone phosphate; Cyclophosphamide; Etoposide; Nivolumab; Doxorubicin; Liposomal doxorubicin; Vincristine
• Other Study ID Numbers: 18-0708.cc

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No