Nivolumab With Standard of Care Chemotherapy for Peripheral T Cell Lymphomas

• ClinicalTrials.gov Identifier: NCT03586999
• Recruitment Status: Recruiting
• First Posted: July 16, 2018
• Last Update Posted: November 8, 2019
• Sponsor: University of Colorado, Denver
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Peripheral T Cell Lymphoma	Drug: Nivolumab and EPOCH	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Nivolumab With Standard of Care Chemotherapy for the First Line Treatment of Peripheral T Cell Lymphoma
• Actual Study Start Date: November 7, 2018
• Estimated Primary Completion Date: August 2020
• Estimated Study Completion Date: August 2021

Arms and Interventions

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 and EPOCH; Nivolumab injection is to be administered as an IV infusion. DA-EPOCH dosage calculations will be based on the patient's body surface area (BSA) at baseline, recommend using 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.

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Start of study to end of study, for up to four years ]
   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.
2. Efficacy: Overall Response Rate [ Time Frame: Start of study to end of study, for up to four years ]
   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.
3. Efficacy: Complete Response Rate [ Time Frame: Start of study to end of study, for up to four years ]
   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.
4. Efficacy: Partial Response Rate [ Time Frame: Start of study to end of study, for up to four years ]
   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.
5. Efficacy: Rate of Stable Disease [ Time Frame: Start of study to end of study, for up to four years ]
   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.
6. Efficacy: Rate of Progressive Disease [ Time Frame: Start of study to end of study, for up to four years ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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 > or = 18.
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, gamma/delta 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 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. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 180 days after the last dose of study treatment. Men must refrain from donating sperm during this same period. 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.
12. 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.

Contacts and Locations

Contacts

Contact: Brad Haverkos; 720-848-0414; bradley.haverkos@ucdenver.edu

Locations

United States, California

City of Hope Cancer Center; Not yet recruiting

Duarte, California, United States, 91010

Contact: Jasmine Zain, MD jazain@coh.org

Principal Investigator: Jasmine Zain, MD

United States, Colorado

University of Colorado Hospital; Recruiting

Aurora, Colorado, United States, 80045

Contact: Derek Schatz 720-848-0628 derek.schatz@ucdenver.edu

Principal Investigator: Brad Haverkos, MD

United States, Pennsylvania

Thomas Jefferson University; Recruiting

Philadelphia, Pennsylvania, United States, 19107

Contact: Pierluigi Porcu, MD pierluigi.porcu@jefferson.edu

Principal Investigator: Pierluigi Porcu, MD

Sponsors and Collaborators

University of Colorado, Denver

Investigators

• Principal Investigator: Brad Haverkos, MD; University of Colorado, Denver

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03586999
• Other Study ID Numbers: 18-0708.cc
• First Posted: July 16, 2018
• Last Update Posted: November 8, 2019
• Last Verified: June 2019

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

Keywords provided by University of Colorado, Denver:

Nivolumab; First Line Treatment; EPOCH; Standard of Care

Additional relevant MeSH terms:

Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents