Nivolumab in Combination With GDP/ L-asparaginase in NK/ T-cell Lymphoma

A Pilot Study of Nivolumab in Combination With GDP (Gemcitabine, Dexamethasone, Cisplatin)/ L-asparaginase in Patients With Advanced Stage or Relapsed/ Refractory Natural-killer/ T-cell Lymphoma

This is a pilot study investigating the role of nivolumab, a PD-1 inhibitor, in the treatment of advanced stage or relapsed/refractory NKTL. Patients who have received PD-1 inhibitors will be excluded from this study.

Patients who have a complete response or good partial response to nivolumab during initial phase will continue to be treated with nivolumab. Patients who have a partial response, stable disease, and progressive disease to nivolumab during initial phase will be treated with the combination of nivolumab and GDP/L-asparaginase.

Study Overview

• Status: Withdrawn
• Conditions: NK/T Cell Lymphoma
• Intervention / Treatment: Drug: IV Nivolumab; Drug: IV Nivolumab; Drug: IV Gemcitabine; Drug: IV Cisplatin; Drug: IV/PO Dexamethasone; Drug: IV L-asparaginase

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore
    • National Cancer Centre Singapore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed written informed consent

  • Subjects must have signed and dated and IRB-approved written consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal subject care
  • Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study

• Target population

  • All subjects must have histologically confirmed extranodal natural-killer/T-cell lymphoma (NKTL)

  • Subjects must have

    • previously untreated stage III or IV NKTL, OR

    • relapsed/refractory NKTL who has received at least 2 cycles of one prior regimen or previous radiotherapy administered with curative intent and one of the following:

      • Failed to achieve at least a partial response
      • Failed to achieve a complete response at the end of planned therapy with curative intent
      • Progressed after initial response
  • Age ≥ 21 years
  • ECOG Performance status 0 - 2

  • Subjects must have laboratory test results within these ranges:

    • Absolute neutrophil count (ANC) ≥ 1.5 x10^9/L
    • Platelet count ≥ 75 x10^9/L
    • Creatinine clearance ≥ 40ml/min
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN). Higher levels are acceptable if these can be attributed to active haemolysis or ineffective erythropoiesis
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2x ULN
• Women of childbearing potential (WOCBT) must agree to use dual methods of contraception and have a negative serum or urine pregnancy test prior study treatment. Male patients must use an effective barrier method of contraception if sexually active with a WOCBT

Exclusion Criteria:

• Previous treatment with an anti PD-1, anti PD-L1, anti PD-L2, anti-CD137, or anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Previous GDP therapy
• Previous serious hypersensitivity reaction or symptomatic pancreatitis from L-asparaginase
• Uncontrolled central nervous (CNS) disease
• Uncontrolled hepatitis B or C
• Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of study drug
• Subjects with > grade 1 peripheral neuropathy
• Any serious or uncontrolled medical disorder, autoimmune disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration or would impair the ability fo the subject to receive the study drug
• Subjects who have had prior malignancies (other than NKTL) for ≤5 year with exception of currently treated basal cell, squamous cell carcinoma of the skin or carcinoma "in situ" of the cervix or breast.
• Subjects who have had other anti-cancer therapy including radiation or experimental drug therapy within 28 days of enrollment
• Subjects with known allergies or hypersensitivities to the study drugs
• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Pregnant women or women who are breastfeeding are excluded from this study

Inclusion of women and minorities:

Men and women of all ethnic groups are eligible for this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab; After 4 doses of nivolumab, if the patient has complete responses (CR) or good partial response (PR), the patient will continue on nivolumab until disease progression, unacceptable toxicities, or discontinuation of treatment. During PET4-directed treatment with single agent nivolumab, if patient has PD, they will proceed to the Nivo+GDP/L-aspa arm.	Drug: IV Nivolumab; 240mg every 2 weeks.; Other Names: Opdivo; Drug: IV Nivolumab; Initial treatment dose is 240mg every 2 weeks for 4 doses. Dose changes to 360mg every 3 weeks when given with GDP/L-aspa. Maintenance treatment dose is 240mg every 2 weeks.; Other Names: Opdivo
Experimental: Nivolumab + GDP/ L-asparaginase; After 4 doses of nivolumab, if the patient has PR, stable disease (SD), or progressive disease (PD), the patient will switch to nivolumab-GDP/L-aspa treatment. After 6 cycles of treatment, if CR is achieved, the patient will continue on single agent nivolumab until disease progression, unacceptable toxicities, or discontinuation of treatment.	Drug: IV Nivolumab; 240mg every 2 weeks.; Other Names: Opdivo; Drug: IV Nivolumab; Initial treatment dose is 240mg every 2 weeks for 4 doses. Dose changes to 360mg every 3 weeks when given with GDP/L-aspa. Maintenance treatment dose is 240mg every 2 weeks.; Other Names: Opdivo; Drug: IV Gemcitabine; 800mg/m2 on Days 1 and 8 every 21 days; Drug: IV Cisplatin; 20mg/m2 on Day 1 to 4 every 21 days; Drug: IV/PO Dexamethasone; 10mg on Days 1 to 4 every 21 days; Drug: IV L-asparaginase; 6000 Units/m2 on Days 2 to 8 every 21 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with complete response and partial response to treatment	To calculate best overall response rate	6 months after the start of treatment
Number of incidences of grade 3-5 non-haematological adverse events	To calculate the toxicity rate of the treatment	From start of first treatment to 100 days after last treatment dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival		From start of treatment to date of disease progression or death, up to 2.5 years
Overall survival		From the start of treatment to date of death from any cause, up to 2.5 years
Number of patients with complete response and partial response to single agent nivolumab	To calculate the overall response rate of single agent nivolumab	6 months after the start of treatment
Number of patients with complete response and partial response to nivolumab in combination with GDP/L-asparaginase		6 months after the start of treatment
Number of incidences of adverse events	To calculate the rate of adverse events from nivolumab with or without GDP/L-asparaginase	From start of first treatment to 100 days after last treatment dose

Collaborators and Investigators

• Sponsor: National Cancer Centre, Singapore
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Tiffany Tang, MD, National Cancer Centre, Singapore

Publications and helpful links

General Publications

• Li X, Cheng Y, Zhang M, Yan J, Li L, Fu X, Zhang X, Chang Y, Sun Z, Yu H, Zhang L, Wang X, Wu J, Li Z, Nan F, Tian L, Li W, Young KH. Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. J Hematol Oncol. 2018 Jan 31;11(1):15. doi: 10.1186/s13045-018-0559-7.
• Kwong YL, Chan TSY, Tan D, Kim SJ, Poon LM, Mow B, Khong PL, Loong F, Au-Yeung R, Iqbal J, Phipps C, Tse E. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017 Apr 27;129(17):2437-2442. doi: 10.1182/blood-2016-12-756841. Epub 2017 Feb 10.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2019
• Primary Completion (Actual): June 12, 2020
• Study Completion (Actual): June 12, 2020

Study Registration Dates

• First Submitted: January 13, 2020
• First Submitted That Met QC Criteria: January 14, 2020
• First Posted (Actual): January 18, 2020

Study Record Updates

• Last Update Posted (Actual): November 5, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• 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; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Gemcitabine; Dexamethasone; Cisplatin; Nivolumab; Asparaginase
• Other Study ID Numbers: CA209-8R6

Drug and device information, study documents

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