Nivolumab for High-Risk MDS/AML Patients After Allogeneic Stem Cell Transplant With Post-Transplant Cyclophosphamide

NCT04361058 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: BMT 30CA209-9WP
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

There are no strategies developed post-stem cell transplant (SCT) for patients who receive allogenic SCT with a significant amount of blasts prior SCT. Novel strategies to treat relapsed AML/MDS and to reduce the incidence of relapse after allogeneic SCT are needed. This study is being done in patients with high-risk MDS or AML who undergo an allogeneic SCT. The study will have two arms, participants who receive an HLA-matched unrelated donor SCT (Arm A) or HLA- haploidentical SCT (Arm B). Following myeloablative conditioning (MAC), GVHD prophylaxis with post-transplantation cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil will be given per standard of care. At 40-60 days post SCT, If the patient has not had any evidence of Grade II-IV acute graft-versus-host-disease (aGVHD), Nivolumab will be given intravenously every 2 weeks for 4 cycles of consolidation or treatment with Nivolumab. Dose-escalation of Nivolumab will follow the standard 3+3 design where a maximum of three dose levels will be evaluated, with a maximum of 18 patients treated with nivolumab per arm. As the maximum tolerated dose (MTD) of Nivolumab may differ between Arm A and Arm B, dose escalation of nivolumab in each arm will be followed separately following allogeneic SCT. Immunosuppression with tacrolimus will be continued during the cycles of PD-1 blockade to provide a moderate level of GVHD prophylaxis during consolidation or treatment with nivolumab.

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myelodysplastic Syndrome Acute Myeloid Leukemia

Keywords

Graft versus host disease; Allogeneic stem cell transplant; Nivolumab; Myelodysplastic syndrome; Acute myeloid leukemia; Post-transplant cyclophosphamide

Outcome Measures

Primary Outcomes (1)

• Incidence of dose limiting toxicities as a determinant of the Maximum Tolerated Dose (MTD)

  Defined as the highest dose at which ≤ 1 of 6 participants experience a DLT. Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease. If 2 or more patients in a dosing group of ≤6 patients experience a DLT, the MTD has been exceeded. If 2 or more patients in a dosing group of up to 6 patients experience a DLT and only 3 patients were evaluated at the previous dose (i.e. next lower). Then, an additional 3 patients will be evaluated at this next lower dose, and if zero or one have DLTs, then this previous dose level is declared the MTD. Dose level -1 will be tested if dose level 1 exceeds the MTD.

  After the first dose of Nivolumab treatment for up to 28 days.

Secondary Outcomes (7)

• Progression-free survival (PFS)

  PFS will be assessed for up to 3 years post-SCT

• Overall survival (OS)

  OS will be assessed for up to 3 years post-SCT

• Number of participants that experience Non-relapse mortality

  Will be assessed throughout study treatment, when study treatment ends, and for up to 3 years

• Number of participants with evidenceof cGVHD

  Will be assessed throughout study treatment, when study treatment ends, and for up to 3 years

• Number of participants that experience Nivolumab-related mortality

  Will be assessed throughout study treatment, when study treatment ends, and for up to 3 years

Study Arms (2)

Arm A - HLA-matched unrelated donor SCT treated with Nivolumab

EXPERIMENTAL

AML/MDS participants who have allogeneic stem cell transplants with an HLA-matched unrelated donor will be separated into Arm A and treated with Nivolumab post-SCT

Drug: Nivolumab

Arm B - HLA-haploidentical donor SCT treated with Nivolumab

EXPERIMENTAL

AML/MDS participants who have allogeneic stem cell transplants with a HLA-haploidentical donor will be separated into Arm B and treated with Nivolumab post-SCT

Drug: Nivolumab

Interventions

Nivolumab DRUG

At Day +50 (±10 days) post-allogeneic SCT, participants will be treated with Nivolumab. Nivolumab will be administered intravenously once every two weeks for a total of 4 treatments. Participants will initially receive nivolumab at a significantly reduced starting dose of 0.25 mg/kg. This dose was determined based on the incidence of increased aGVHD, which was noted after treatment post-SCT in previous studies. Nivolumab IV will be given every 2 weeks for 4 cycles. One dose of nivolumab is equivalent to one cycle. The first administration will be at Day +50 (±10 days), assuming the participant has not had any evidence of Grade II-IV aGVHD after allogeneic SCT and does not have any current evidence of any grade of aGVHD at the day of first application of nivolumab. Depending on emerging safety data, dose escalation cohorts will explore higher dose levels of nivolumab at 0.5 mg/kg and 1 mg/kg.

Also known as: Opdivo

Arm A - HLA-matched unrelated donor SCT treated with Nivolumab; Arm B - HLA-haploidentical donor SCT treated with Nivolumab

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent form (ICF), according to local guidelines, signed by the patient or by a legal guardian prior to the performance of any study-related screening procedures (i.e., prior to conditioning).
• Male and female patients between ≥18 and ˂66 years-of-age
• Patients with high-risk AML defined as: AML with ≥5% bone marrow blast burden prior to allogeneic SCT who failed ≥2 lines of cytoreductive anti-leukemic therapy
• Patients with high risk MDS defined as: MDS with ≥10% bone marrow blasts prior to allogeneic SCT despite 1 line of prior cytoreductive anti-leukemic treatment with chemotherapy or hypomethylating agent
• Patients will receive a MAC MUD or MAC haploidentical SCT followed by PTCy as treatment for AML or MDS.
• A 10/10 HLA-match is required for patients that will receive a MUD SCT.
• A 5/10 HLA-match or greater is required for patients that will receive a haploidentical SCT.
• Patients must be able to swallow and retain oral medication.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or
• Patients who have achieved a CR post-allogeneic SCT
• Patients who have persistent disease post-allogeneic SCT
• Greater than 50% PB donor T cell chimerism
• Adequate renal function defined as serum creatinine ≤2.0 mg/dL or creatinine clearance ≥40 mL/min measured or calculated by Cockcroft-Gault equation.
• Females of childbearing potential must have a negative serum or urine pregnancy test result within 72 hours prior to the first dose of nivolumab and must agree to follow instructions for method(s) of contraception, using two forms of acceptable contraception, including one barrier method, for the duration of treatment with nivolumab and for 7 months following their last dose of the study drug. Females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy.
• Male patients with female partners of childbearing potential are required to use contraceptive methods, during their participation in the study and for 7 months following the last dose of study drug. Male patients must also refrain from donating sperm during their participation in the study and for 7 months following the last dose of study drug.

You may not qualify if:

• Prior allogeneic SCT
• Pregnant or lactating women
• Evidence of active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of active infection progression are present. This is assessed by the site clinicians including consulting physicians from infectious disease regarding adequacy of therapy. These infections include, but are not limited to:
• Known human immunodeficiency virus (HIV) infection
• Active tuberculosis infection
• History of autoimmune pneumonitis within the last 5 years
• Prior diagnosis of an inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
• History of severe hypersensitivity reactions to monoclonal antibodies
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
• Current evidence of any grade of active aGVHD at Day 40-60 at the time of study enrollment
• Prior history of Grade II or higher aGVHD (Appendix E)
• Prior or concurrent treatment with DLI
• Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of nivolumab, except antimicrobial drugs. For study drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the study drug and administration of nivolumab is required, except antimicrobial drugs.
• Evidence of active uncontrolled bacterial, fungal, parasitic, or viral infection. Infections are considered controlled if appropriate therapy has been instituted and, at the time of screening, no signs of infection progression are present.
• Active autoimmune disease that has persisted or recurred after allogeneic SCT, except vitiligo or resolved childhood asthma/atopy.

Sponsors & Collaborators

• SCRI Development Innovations, LLC: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Colorado Blood Cancer Institute

Denver, Colorado, 80218, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; GATA2 Deficiency; Graft vs Host Disease

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 15, 2020
• First Posted: April 24, 2020
• Study Start: April 13, 2020
• Primary Completion: April 20, 2021
• Study Completion: April 20, 2021
• Last Updated: December 5, 2023

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)