Clinical trial NCT01822509: Ipilimumab or Nivolumab in Treating Patients With Relapsed Hematologic Malignancies After Donor Stem Cell Transplant
Official title: A Phase I/IB Study of Ipilimumab or Nivolumab in Patients With Relapsed Hematologic Malignancies After Allogeneic Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Allogeneic Hematopoietic Stem Cell Transplant Recipient
Myeloproliferative Neoplasm
Recurrent Acute Lymphoblastic Leukemia
Recurrent Acute Myeloid Leukemia
Recurrent Chronic Lymphocytic Leukemia
Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Recurrent Hematologic Malignancy
Recurrent Hodgkin Lymphoma
Recurrent Myelodysplastic Syndrome
Recurrent Non-Hodgkin Lymphoma
Recurrent Plasma Cell Myeloma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2013-04-02
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/Ib trial studies the side effects and best dose of ipilimumab or nivolumab in treating patients with cancers of the blood and blood-forming tissues (hematologic cancers) that have returned after a period of improvement (relapsed) after donor stem cell transplant. Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) of ipilimumab or nivolumab administered to patients with relapsed hematologic malignancies following allogeneic stem cell transplantation. (Phase I) II. To characterize the toxicity of ipilimumab or nivolumab administered at the MTD in this patient population. (Phase Ib)

SECONDARY OBJECTIVES:

I. To assess response rate. II. To assess progression free and overall survival.

EXPLORATORY OBJECTIVE:

I. To assess the phenotypic and functional effects of ipilimumab or nivolumab on immune cells.

OUTLINE: This is a dose-escalation study.

INDUCTION PHASE: Patients receive ipilimumab intravenously (IV) over 90 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 14 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE PHASE: Patients receive ipilimumab IV over 90 minutes. Treatment repeats every 12 weeks beginning at cycle 5 (24 weeks after the first dose of ipilimumab) for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients achieving clinical benefit will have the option to continue with ongoing maintenance dosing every 12 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes every 2 weeks in the absence of disease progression or unacceptable toxicity. Treatment repeats every 14 days for up to a total of 60 weeks (including Induction) in the absence of disease progression or unacceptable toxicity.

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

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed hematologic malignancy
* The following malignancies will be considered eligible if progressive or persistent:

  * Chronic lymphocytic leukemia (CLL)
  * Non-Hodgkin lymphoma (NHL)
  * Hodgkin lymphoma (HL)
  * Multiple myeloma (MM)
  * Acute leukemia (acute myeloid leukemia \[AML\], acute lymphoblastic leukemia \[ALL\])
  * Myelodysplastic syndrome (MDS)
  * Myeloproliferative neoplasms (MPN)
  * Chronic myeloid leukemia (CML)
* Life expectancy of greater than 3 months
* Must have undergone allogeneic hematopoietic stem cell transplantation (HSCT) (regardless of stem cell source)
* Must have baseline donor T cell chimerism of \>= 20%
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (unless due to Gilbert's disease or disease-related hemolysis, then =\< 3.0 x ULN)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 x institutional ULN
* Creatinine =\< 1.5 x institutional ULN
* Prednisone dose =\< 5 mg/day and off all other systemic immunosuppressive medications for at least 4 weeks prior to study entry
* Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

* Participants who have had anti-tumor therapy or other investigational agents within 4 weeks prior to registration (6 weeks for nitrosoureas or mitomycin C), or those who have not recovered from adverse events due to agents administered more than 4 weeks prior to registration
* Patients with prior history of or active severe (grade 3 or 4) acute graft-versus-host disease (GVHD)
* Patients with a history of prior treatment with ipilimumab, anti-programmed cell death protein 1 (PD 1) antibody, or cluster of differentiation (CD)137 agonist therapy are ineligible for the ipilimumab arm, but are eligible for the nivolumab arm
* Patients who have had donor lymphocyte infusion (DLI) within 8 weeks prior to registration
* Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's granulomatosis\]) and motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre syndrome and myasthenia gravis); patients with Hashimoto's thyroiditis are eligible to go on study
* Patients with known chronic human immunodeficiency virus (HIV), hepatitis B or hepatitis C infections should be excluded
* 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
* Pregnant women are excluded from this study because ipilimumab and nivolumab are immunomodulatory agents with the potential for teratogenic or abortifacient effects; the effects of ipilimumab and nivolumab on the developing human fetus are unknown; for this reason and because immunomodulatory agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study or within 23 weeks after the last dose of study drug, 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 for at least 31 weeks after completion of ipilimumab or nivolumab administration

Primary outcomes:
measure: Maximum tolerated dose (MTD) of ipilimumab according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Phase I)
timeFrame: At 12 weeks
measure: Maximum tolerated dose (MTD) of nivolumab according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Phase I)
timeFrame: At 12 weeks
measure: Incidence of adverse events as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (Phase Ib)
timeFrame: Up to 1 year after completion of study treatment
Secondary outcomes:
measure: Clinical response
timeFrame: Up to 1 year
measure: Progression-free survival (PFS)
timeFrame: From start of treatment to time of objective disease progression, assessed up to 1 year
measure: Overall survival (OS)
timeFrame: From the start of treatment to time of death, assessed up to 1 year
Other outcomes:
measure: Change in immune cell numbers
timeFrame: Baseline to up to 1 year
measure: Change in cytokine production
timeFrame: Baseline to up to 1 year
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: South Pasadena
country: United States
facility: City of Hope South Pasadena
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Tampa
country: United States
facility: Moffitt Cancer Center-International Plaza
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Brewer
country: United States
facility: Lafayette Family Cancer Center-EMMC
state: Maine
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Charlestown
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Matthew S Davids
role: PRINCIPAL_INVESTIGATOR
References:
citation: Penter L, Zhang Y, Savell A, Huang T, Cieri N, Thrash EM, Kim-Schulze S, Jhaveri A, Fu J, Ranasinghe S, Li S, Zhang W, Hathaway ES, Nazzaro M, Kim HT, Chen H, Thurin M, Rodig SJ, Severgnini M, Cibulskis C, Gabriel S, Livak KJ, Cutler C, Antin JH, Nikiforow S, Koreth J, Ho VT, Armand P, Ritz J, Streicher H, Neuberg D, Hodi FS, Gnjatic S, Soiffer RJ, Liu XS, Davids MS, Bachireddy P, Wu CJ. Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation. Blood. 2021 Jun 10;137(23):3212-3217. doi: 10.1182/blood.2021010867.
citation: Davids MS, Kim HT, Costello C, Herrera AF, Locke FL, Maegawa RO, Savell A, Mazzeo M, Anderson A, Boardman AP, Weber A, Avigan D, Chen YB, Nikiforow S, Ho VT, Cutler C, Alyea EP, Bachireddy P, Wu CJ, Ritz J, Streicher H, Ball ED, Bashey A, Soiffer RJ, Armand P. A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation. Blood. 2020 Jun 11;135(24):2182-2191. doi: 10.1182/blood.2019004710.
citation: Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, Lukez AP, Avigan D, Chen YB, McSweeney P, LeBoeuf NR, Rooney MS, Bowden M, Zhou CW, Granter SR, Hornick JL, Rodig SJ, Hirakawa M, Severgnini M, Hodi FS, Wu CJ, Ho VT, Cutler C, Koreth J, Alyea EP, Antin JH, Armand P, Streicher H, Ball ED, Ritz J, Bashey A, Soiffer RJ; Leukemia and Lymphoma Society Blood Cancer Research Partnership. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N Engl J Med. 2016 Jul 14;375(2):143-53. doi: 10.1056/NEJMoa1601202.