Clinical Trials/NCT02846376

NCT02846376

Terminated

Phase 1

Phase I Study of Single-agent and Combined Checkpoint Inhibition After Allogeneic Hematopoietic Stem Cell Transplantation in Patients at High Risk for Post-transplant Recurrence

Hackensack Meridian Health1 site in 1 country8 target enrollmentMarch 8, 2019

ConditionsAcute Myeloid Leukemia and Myelodysplastic Syndrome

InterventionsNivolumab Ipilimumab

DrugsNivolumab Ipilimumab

Overview

Phase: Phase 1
Intervention: Nivolumab
Conditions: Acute Myeloid Leukemia and Myelodysplastic Syndrome
Sponsor: Hackensack Meridian Health
Enrollment: 8
Locations: 1
Primary Endpoint: Safety: The occurrence of at least one treatment-related limiting toxicity defined as a ≥ grade 4 non-hematologic toxicity as specified by the CTCAE 4.0.
Status: Terminated
Last Updated: last year

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Sites Similar Trials

Overview

Brief Summary

The purpose of the study is to determine the safety and benefit of nivolumab, ipilimumab or the combination of nivolumab with ipilimumab given after bone marrow transplant for patients with acute myelogenous leukemia and myelodysplastic syndrome.

Detailed Description

The primary objectives of this study are: * To assess the safety of single-agent and combined checkpoint inhibition with nivolumab and ipilimumab in patients with acute myelogenous leukemia and myelodysplastic syndrome who have undergone hematopoietic stem cell transplantation and are at high risk for post-transplant recurrence. * Safety endpoint: The composite endpoint consisting of the occurrence of at least one treatment-related limiting toxicity (after checkpoint inhibitor treatment is initiated) defined as a ≥ grade 4 non-hematologic toxicity as specified by the CTCAE. Exceptions listed in section 5.9 apply to this endpoint as well. If 3 of 7 patients in a single cohort experience a treatment-related limiting toxicity, that single cohort will be terminated.

Registry

clinicaltrials.gov

Start Date

March 8, 2019

End Date

December 21, 2023

Last Updated

last year

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Hackensack Meridian Health

Responsible Party

Sponsor

Eligibility Criteria

Inclusion Criteria

•Voluntary signed and dated IRB/IEC approved written informed consent form in accordance with regulatory and local guidelines.
•Be 18 years or older and 70 years or younger on the day of signing consent
•Have a confirmed diagnosis of non-M3 acute myeloid leukemia (AML) (Intermediate-II is high risk. Our population will consist of Intermediate-II and high risk patients or any FLT3+ AML) or IPSS intermediate -2 or high risk myelodysplastic syndrome (MDS) (Appendices A and B).
•Have an available 6/6 related donor or an unrelated donor with a 10/10 match for HLA-A, B, C, DRB1 and DQ antigen who consents to provide a marrow or peripheral blood stem cell allograft. Typing is by DNA techniques: intermediate resolution for A, B and C, and high resolution for DRB1/DQ
•Be receiving one of the following conditioning regimen: fludarabine at a dose of 30 mg/m2 IV daily for 5 days, busulfan at a dose of 130 mg/m2 IV daily for 2 days, and rabbit antithymocyte globulin (ATG) at a dose of 2 mg/kg IV daily for 2 days OR fludarabine at a dose of 30 mg/m2 IV daily for 4 days, melphalan at a dose of 140 mg/m2 for one day with or without ATG at a dose of 2 mg/kg IV daily for 2 days
•Be deemed eligible for an allogenic stem cell transplantation as per institutional guidelines of the Blood and Marrow Transplantation Program at John Theurer Cancer Center at Hackensack University Medical Center
•Patients with adequate organ function as measured by:
•Cardiac: left ventricular ejection fraction at rest \> 50%
•Hepatic: serum total bilirubin \< 1.5x upper limit of normal for age as per local laboratory (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome); ALT and AST \< 4x upper limit of normal for age as per local laboratory
•Renal: serum creatinine \< 2x upper limit of normal for age (as per local laboratory). For patients with serum creatinine above the normal range, a glomerular filtration rate (measured as per institutional practice, typically creatinine clearance) equal to or greater than 60 mL/min (corrected to 1.73m2 body surface area) is required.

Exclusion Criteria

•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. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (\> 20 mg/day prednisone equivalents) for at least 4 weeks prior to study drug administration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \> 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
•Is unable or unwilling to sign informed consent.
•Has an active, known, or suspected autoimmune disease. Subjects 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
•Patients should be excluded if they have a condition such as GVHD requiring systemic treatment with either corticosteroids (\> 20 mg daily prednisone equivalents) or other immunosuppressive medications within 4 weeks of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 20 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalation corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \> 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
•As there is potential for hepatictoxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen.
•Has received a prior allogeneic stem cell transplant.
•Has a history of hypersensitivity to nivolumab, ipilimumab, or any of its excipients, or severe hypersensitivity reaction to any previous monoclonal antibody.
•Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Day 1 of checkpoint inhibitor treatment administration or who has not recovered (i.e., t administration mAb) within 4 weeks prior to t dose of trial treatment. Rituximab within that time frame is allowed.
•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 (eg. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Note: Subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if \> 20 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
•Has known history of, or any evidence of active, non-infectious pneumonitis.

Arms & Interventions

Group A - Nivolumab

Nivolumab for 12 doses, on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 * Dose level 1: 1 mg/kg * Dose level 2: 3 mg/kg

Intervention: Nivolumab

Group B - Ipilimumab

Ipilimumab for 6 doses on day 1 of weeks 1, 4, 7, 10, 13, 16 * Dose level 1: 0.3 mg/kg * Dose level 2: 1.0 mg/kg * Dose level 3: 3.0 mg/kg

Intervention: Ipilimumab

Group C - Nivolumab + Ipilimumab

* Nivolumab 3 mg/kg for 12 doses, on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 * Ipilimumab for 6 doses on day 1 of weeks 1, 4, 7, 10, 13, 16 * Dose level 1: 0.3 mg/kg * Dose level 2: 0.6 mg/kg * Dose level 3: 1.0 mg/kg

Intervention: Nivolumab

Group C - Nivolumab + Ipilimumab

Intervention: Ipilimumab

Outcomes

Primary Outcomes

Safety: The occurrence of at least one treatment-related limiting toxicity defined as a ≥ grade 4 non-hematologic toxicity as specified by the CTCAE 4.0.

Time Frame: After treatment is initiated through 100 days of discontinuation of dosing.

Exceptions are: Isolated Grade 4 amylase or lipase values that are not associated with symptoms or clinical manifestations of pancreatitis and decrease to \< Grade 4 within 1 week of onset and isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are corrected with supplementation/appropriate management within 72 hours of their onset. If 3 of 7 patients in a single cohort experience a treatment-related limiting toxicity, that single cohort will be terminated.

Secondary Outcomes

Assessment of blood phenotype(At consent for subjects and within 30 days pre allogeneic transplant conditioning for donors, at apheresis, and day 1 of week 1 of protocol tx and weeks 4,7,12,18,26, and at 9,12,15,18 months post-transplant and at relapse if within 18 months of tx.)
Efficacy as assessed by progression free survival (PFS)(At 18 months after treatment is initiated)
Toxicities: Common Terminology Criteria for Adverse Events (CTCAE) will be used for the assessment and grading of all toxicities experienced by patients enrolled into this study.(Through 100 days of discontinuation of dosing.)
Assessment of blood immune reconstitution by sequencing to determine diversity and highest frequency clonal specificities(At consent for subjects and within 30 days pre allo transplant conditioning for donors, at apheresis, and day 1 of week 1 of protocol treatment (tx) and then weeks 4,7,12,18,26, and at 9,12,15,18 mos post-transplant and at relapse if within 18 mos of tx.)
Tumor site immune phenotyping(If bone marrow biopsy is available prior to allogeneic transplantation conditioning and then at time of relapse within 18 months following initiation of therapy.)
Assessment of complete response (CR) rate(Assess at 3, 6 and 12 months after transplant)
Assessment of blood TCR repertoire via TCR Immunoseq Assay Profiling(At consent for subjects and within 30 days pre allogeneic transplant conditioning for donors, at apheresis, and day 1 of week 1 of protocol tx and weeks 4,7,12,18,26, and at 9,12,15,18 months post-transplant and at relapse if within 18 months of tx.)
Assess tumor site TCR repertoire using Poisson regression analysis with generalized estimating equations (GEE)(When bone marrow biopsy is available prior to allogeneic transplantation conditioning and then at time of relapse within 18 months following initiation of therapy.)
Assess tumor site PD-L1/2 expression(When bone marrow biopsy is available prior to allogeneic transplantation conditioning and then at time of relapse within 18 months following initiation of therapy.)