Nivolumab in Treating Patients With HTLV-Associated T-Cell Leukemia/Lymphoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02631746
• Collaborator: (none)
• Enrollment: 3
• Locations: 8
• Arm: 1
• Actual Duration (Months): 13.2
• Patients Per Site: 0.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies how well nivolumab works in treating patients with human T-cell leukemia virus (HTLV)-associated T-cell leukemia/lymphoma. Nivolumab is an antibody, which is a type of blood protein that tags infected cells and other harmful agents. Nivolumab works against a protein called programmed cell death (PD)-1 and may help the body destroy cancer cells by helping the immune system to keep fighting cancer.

Condition or Disease	Intervention/Treatment	Phase
Acute Adult T-Cell Leukemia/Lymphoma; Adult T-Cell Leukemia/Lymphoma; Chronic Adult T-Cell Leukemia/Lymphoma; HTLV-1 Infection; Lymphomatous Adult T-Cell Leukemia/Lymphoma; Smoldering Adult T-Cell Leukemia/Lymphoma	Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Other: Pharmacogenomic Study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the safety and tolerability of nivolumab for patients with HTLV-associated adult T-cell leukemia lymphoma (ATLL).

2. To determine the efficacy of nivolumab for patients with HTLV-associated ATLL.

SECONDARY OBJECTIVES:

1. To determine effects of nivolumab on HTLV-1 proviral deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) loads.

2. To determine the effects of nivolumab on anti-HTLV-1 and anti-ATLL immune responses.

3. To determine effects of nivolumab on HTLV-1 integration site clonality.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Nivolumab for HTLV-Associated Adult T Cell Leukemia/Lymphoma
• Actual Study Start Date: Feb 21, 2017
• Actual Primary Completion Date: Nov 30, 2017
• Actual Study Completion Date: Mar 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (nivolumab) Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558 MDX-1106 NIVO ONO-4538 Opdivo ; Other: Pharmacogenomic Study; Correlative studies; Other Names: PHARMACOGENOMIC

Outcome Measures

Primary Outcome Measures

1. Incidence of Adverse Events of Nivolumab, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [1 year]

   Toxicity by grade will be summarized using descriptive statistics. The incidence of toxicities will be estimated using the binomial proportion and its 90% confidence interval.

2. Tumor Response, Evaluated Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors Guideline (Version 1.1) [1 year]

   Summarized using descriptive statistics. Binomial proportions and their 90% confidence intervals will be used to estimate the response rates of therapy.

3. Duration of Response [1 year]

   Summarized using descriptive statistics. Binomial proportions and their 90% confidence intervals will be used to estimate the response rates of therapy. The Kaplan-Meier method will be used to evaluate the response duration.

Secondary Outcome Measures

1. Effects of Treatment [1 year]

   Analysis of variance methods will be used to evaluate the effects of treatment.

2. Time on the Viral Load Measurements [1 year]

   Analysis of variance methods will be used to evaluate the effects of treatment and time on the viral load measurements, as well as measurements of viral transcripts. A proportional hazards analysis with viral load measures as time dependent covariates will be used to evaluate the effects of these measures on duration of response.

3. HTLV-1 Clonality [1 year]

   Measured from peripheral blood mononuclear cell (PBMC) samples.

4. HTLV-1 Specific Cytotoxic T Lymphocytes (CTLs) [1 year]

   Measured from PBMC samples.

5. Immune Cell Numbers [1 year]

   Measured from blood and tissue samples.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with any stage of pathologically confirmed cluster of differentiation (CD)3+ acute, lymphoma, chronic, or smoldering subtypes of ATLL

• Documentation of HTLV infection (enzyme linked immunosorbent assay [ELISA]) in individual with confirmation of HTLV-1 infection (by immunoblot or polymerase chain reaction [PCR]) or a consistent clinical picture (including two of the following: 1) CD4+ leukemia or lymphoma, 2) hypercalcemia, and/or 3) Japanese, Caribbean or South American birthplace)

• Patients with acute or lymphoma forms must have received at least one cycle of combination chemotherapy (with or without mogamulizumab) or interferon (with or without zidovudine and/or arsenic); individuals with chronic or smoldering acute T-cell lymphoma (ATL) are not required to have had prior treatment or could have received any number of previous courses of therapy

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 60%)

• Life expectancy > 12 weeks

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin within normal institutional limits

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal

• Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation; women should continue birth control for 23 weeks after stopping nivolumab, and men should continue birth control for 31 weeks after stopping nivolumab; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 31 weeks after completion of nivolumab administration

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab

• Prior allogeneic transplantation

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Any condition requiring > 10 mg/d prednisone equivalents

• Current or prior HTLV-1 associated inflammatory diseases, including but not limited to myelopathy, uveitis, arthropathy, pneumonitis, or a Sjogren's disease-like disorder

• Prior treatment with anti-PD-1, anti-programmed death-ligand (PD-L)1, anti-PD-L2 antibody

• Grade 2 or greater toxicity from prior therapy

• Grade 2 or greater diarrhea

• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies (other than HTLV-associated arthropathy), and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible; patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)

• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study

• Patients who have hepatitis C (both reactive anti-hepatitis C virus [HCV] antibody and detectable HCV RNA) and hepatitis B (hepatitis B surface antigen [HBsAg] positive and anti-hepatitis B core [HBc]-total positive), may be enrolled, provided their total bilirubin: =< 1.5 x institutional upper limit of normal (ULN) AST (SGOT)/ALT (SGPT): =< 2.5 x institutional upper limit of normal

• Patients with concurrent human immunodeficiency virus (HIV) infection may be enrolled if compliant with 3 or more drug anti-retroviral regimen and virus load less than 50 copies/ml and CD4 count greater than 250 cells/ml, and no concurrent opportunistic infection or other malignancy

• Any other prior malignancy from which the patient has been disease free for less than 3 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of any site or any other cancer

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with nivolumab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
2	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892
3	NCI - Center for Cancer Research	Bethesda	Maryland	United States	20892
4	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
5	Montefiore Medical Center-Einstein Campus	Bronx	New York	United States	10461
6	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
7	Duke University Medical Center	Durham	North Carolina	United States	27710
8	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Lee Ratner, Duke University - Duke Cancer Institute LAO

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 27, 2017

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02631746
• Other Study ID Numbers: NCI-2015-02126; NCI-2015-02126; 125462; 9925; 9925; UM1CA186704
• First Posted: Dec 16, 2015
• Last Update Posted: Dec 11, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: HTLV-I Infections; Lymphoma; Leukemia; Leukemia, T-Cell; Leukemia-Lymphoma, Adult T-Cell; Nivolumab

Study Results

Participant Flow

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Period Title: Overall Study
STARTED	3
COMPLETED	0
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Overall Participants	3
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51 (8.9)
Sex: Female, Male (Count of Participants)
Female	2 66.7%
Male	1 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 33.3%
Not Hispanic or Latino	1 33.3%
Unknown or Not Reported	1 33.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 33.3%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	2 66.7%
Region of Enrollment (Count of Participants)
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Adverse Events of Nivolumab, Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Description	Toxicity by grade will be summarized using descriptive statistics. The incidence of toxicities will be estimated using the binomial proportion and its 90% confidence interval.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Measure Participants	3
Count of Participants [Participants]	3 100%

2. Primary Outcome

Title	Tumor Response, Evaluated Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors Guideline (Version 1.1)
Description	Summarized using descriptive statistics. Binomial proportions and their 90% confidence intervals will be used to estimate the response rates of therapy.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Measure Participants	3
Count of Participants [Participants]	0 0%

3. Primary Outcome

Title	Duration of Response
Description	Summarized using descriptive statistics. Binomial proportions and their 90% confidence intervals will be used to estimate the response rates of therapy. The Kaplan-Meier method will be used to evaluate the response duration.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Duration of response cannot be calculated because of no responders.

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Measure Participants	0

4. Secondary Outcome

Title	Effects of Treatment
Description	Analysis of variance methods will be used to evaluate the effects of treatment.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Post-treatment data not available because no patients made it to Cycle 3 Day 1.

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Measure Participants	0

5. Secondary Outcome

Title	Time on the Viral Load Measurements
Description	Analysis of variance methods will be used to evaluate the effects of treatment and time on the viral load measurements, as well as measurements of viral transcripts. A proportional hazards analysis with viral load measures as time dependent covariates will be used to evaluate the effects of these measures on duration of response.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Post-treatment data not available because no patients made it to Cycle 3 Day 1.

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Measure Participants	0

6. Secondary Outcome

Title	HTLV-1 Clonality
Description	Measured from peripheral blood mononuclear cell (PBMC) samples.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Post-treatment data not available because no patients made it to Cycle 3 Day 1.

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Measure Participants	0

7. Secondary Outcome

Title	HTLV-1 Specific Cytotoxic T Lymphocytes (CTLs)
Description	Measured from PBMC samples.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Post-treatment data not available because no patients made it to Cycle 3 Day 1.

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Measure Participants	0

8. Secondary Outcome

Title	Immune Cell Numbers
Description	Measured from blood and tissue samples.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Post-treatment data not available because no patients made it to Cycle 3 Day 1.

Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	1 year
Arm/Group Title	Treatment (Nivolumab)
Arm/Group Description	Patients receive nivolumab IV over 60 minutes on day 1. Treatment repeats every 14 days for 46 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nivolumab: Given IV Pharmacogenomic Study: Correlative studies
All Cause Mortality
	Treatment (Nivolumab)
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Treatment (Nivolumab)
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Splenomegaly/splenic infarct	1/3 (33.3%)
Gastrointestinal disorders
Abdominal Pain	1/3 (33.3%)
Investigations
Alanine aminotransferase increased	1/3 (33.3%)
Aspartate aminotransferase increased	2/3 (66.7%)
Metabolism and nutrition disorders
Hypercalcemia	2/3 (66.7%)
Renal and urinary disorders
Acute kidney injury	1/3 (33.3%)
Other (Not Including Serious) Adverse Events
	Treatment (Nivolumab)
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)
Cardiac disorders
Sinus tachycardia	1/3 (33.3%)
Gastrointestinal disorders
Nausea	1/3 (33.3%)
Vomiting	1/3 (33.3%)
General disorders
Fatigue	1/3 (33.3%)
Fever	1/3 (33.3%)
Investigations
Alanine aminotransferase increased	1/3 (33.3%)
Alkaline phosphatase increased	1/3 (33.3%)
Blood bilirubin increased	1/3 (33.3%)
Creatinine increased	1/3 (33.3%)
INR increased	1/3 (33.3%)
Neutrophil count decreased	1/3 (33.3%)
Platelet count decreased	1/3 (33.3%)
Metabolism and nutrition disorders
Anorexia	1/3 (33.3%)
Hyperglycemia	1/3 (33.3%)
Hypoalbuminemia	1/3 (33.3%)
Hypokalemia	1/3 (33.3%)
Hypophosphatemia	1/3 (33.3%)
Musculoskeletal and connective tissue disorders
Bone pain	1/3 (33.3%)
Myalgia	1/3 (33.3%)
Renal and urinary disorders
Acute kidney injury	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary edema	1/3 (33.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.