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Cyclophosphamide

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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

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

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.

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.

There are no strategies developed post SCT for patients who receive allogenic SCT with a significant amount of blasts prior SCT. Historically, the risk of relapse for patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is estimated to be 60% to 80%. No standard consolidation treatment options for patients with AML/MDS have been established to decrease the risk of relapse. The options are also limited for patients with relapsed disease after allogeneic SCT. Thus, novel strategies to treat relapsed disease and to reduce the incidence of relapse after allogeneic SCT are needed. PD-1 inhibition can induce remission in patients with relapsed hematologic disease after allogeneic SCT, but the major risk of PD-1 blockade after allogeneic SCT remains the promotion of severe GVHD leading to death. Alternative approaches are needed to reduce the incidence of GVHD after PD-1 blockade while maintaining a strong graft-versus-tumor (GVT) effect. Adding post-transplantation cyclophosphamide (PTCy) prior to PD-1 blockade after an allogeneic SCT may potentially reduce the expected incidence of acute GVHD and prevent relapse by enhancing the GVT effect. As the absence of GVHD has been associated with increased incidence of relapse, it is reasonable to investigate high-risk patients in CR without evidence of GVHD after allogeneic SCT. Since early relapse or progression of disease after allogeneic SCT is associated with a very poor outcome and treatment options are limited, it is also reasonable investigate patients with persistent or progressive disease after allogeneic SCT. At present, no prospective studies have been conducted post-allogeneic SCT using PTCy followed by PD-1 inhibition as a consolidation therapy or as a therapy for persistent or progressive disease. PD-1 blockade after PTCy appears to be safe and does not induce GVHD when compared to patients who did not receive PD-1 blockade after PTCy. As a means to reduce the risk of relapse or provide potentially effective treatment for persistent/progressive disease, this strategy may also avoid the harm of inducing GVHD or possibly exacerbating previously existing GVHD.

This is a multi-center, open-label, double-arm Phase I dose-escalation study of patients with high-risk MDS and AML prior to receiving allogeneic SCT. A maximum of 36 patients (maximum 18 patients per arm) are planned to be screened and enrolled prior to allogeneic SCT with the expectation that each patient will be a suitable candidate for study participation at the time of administration of nivolumab.

Following myeloablative conditioning (MAC) and HLA-matched unrelated donor SCT (Arm A) or HLA- haploidentical SCT (Arm B), GVHD prophylaxis with PTCy, tacrolimus and mycophenolate mofetil will be given per standard of care.

At 40-60 days post SCT, patients without evidence of aGVHD will begin 4 cycles of consolidation or treatment with nivolumab. 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.

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. 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. 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 patient 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.

Participants will be followed for up to 1 year post-SCT and have long-term follow-up will be from 1.5 up to 3 years post-SCT for adverse events, progression or relapse, survival, and evidence of GVHD.

Chronic GVHD staging and grading will be assessed for efficacy as per National Institutes of Health Consensus criteria. Safety and tolerability will be assessed as per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03.

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

Graft-Versus-Tumor Augmentation With Nivolumab for High-Risk Patients With MDS and AML After Allogeneic Stem Cell Transplantation Using Post-Transplantation Cyclophosphamide

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.

Defined as the time from the first day of study drug administration until the date of relapse, progression, or death from any cause; patients not known to have relapsed/progressed or died at last follow-up are censored on the date they were last examined. Progression is defined as evidence for an increase in bone marrow blast percentage and/or increase of absolute blast counts in the blood: \>50% increase in marrow blasts over baseline (min 15% increase is required in cases with \<30% blasts at baseline); or persistent marrow blast percentage of \>70% over at least 3 months; without at least a 100% improvement in absolute neutrophil count (ANC) to an absolute level \[\>0.5 x 109/L (500/μL), and/or platelet count to \>50 x 109/L (50,000/μL) non-transfused\]; or \>50% increase in peripheral blasts (WBC x % blasts) to \>25 x 109/L (\>25,000/μl) (in the absence of differentiation syndrome); or New extramedullary disease.

Defined as the time from the first day of study drug administration to death on study from any cause or study discontinuation.

Defined as death in the absence of recurrent or progressive malignancy after stem cell transplant (SCT).

Number of participants with evidence/cumulative incidence of chronic GVHD (\>0 cGVHD symptoms on the chronic GVHD activity assessment form) at 1 year and up to 3 years post-SCT.

Number of participants with mortality directly related to nivolumab leading to Grade III-IV aGVHD or non-GVHD immune-mediated toxicity leading to death.

Number of participants (cumulative incidence) who achieve a complete remission (CR) or CR with incomplete hematologic recovery (CRi) who later relapse (Bone marrow blasts ≥5%; or reappearance of blasts in the blood; or development of extramedullary disease) measured from the date of achievement of a remission until the date of relapse.

Defined as the time measured from the date of achievement of a remission until the date of relapse (bone marrow blasts ≥5%; or reappearance of blasts in the blood; or development of extramedullary disease) or death from any cause; only for patients achieving complete remission (CR), or CR with incomplete hematologic recovery (CRi); patients not known to have relapsed or died at last follow-up are censored on the date they were last examined.

Bristol-Myers Squibb

SCRI Development Innovations, LLC

Azacitidine

Antimetabolites

Enzyme Inhibitors

AB8939 administered in combination with azacitidine

Intravenous injection (from an initial dose of 0.9 mg/m²)

AB8939

Clinical Study Coordinator

Norbert Vey, MD

Nicholas Short, MD

The primary objective is to define the safety and tolerability of AB8939 in patients with AML by determining the dose-limiting toxicities, the maximum tolerated dose, and the recommended dose for dose expansion study.

This is a Phase 1/2, open-label, multi-center, non-randomized, 2-part study in patients with refractory and relapsed AML and refractory myelodysplastic syndrome.

Study AB18001 has a multi-stage design. The first part is a dose escalation study that aims to determine the safety, tolerability and pharmacokinetic profiles of consecutive daily intravenous administration of AB8939 in patients with refractory or relapsed AML or patients with refractory myelodysplastic syndrome, and to determine the recommended dose for the second-stage dose expansion study. This dose expansion study aims to determine the schedule for a Phase 2 trial in patients with relapsed/refractory AML and to also provide an early efficacy assessment of AB8939.

Open-label, multi-centre, non-randomized, 2-part study

AB8939 in Patients With Relapsed/Refractory Acute Myeloid Leukemia

A Phase 1/2 Study to Assess the Safety, Pharmacokinetics, and Efficacy of Daily Intravenous AB8939 in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Identification of the Maximal Tolerated Dose for different dosing schedules

The proportion of patients who have a partial or complete response to therapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nivolumab for High-Risk MDS/AML Patients After Allogeneic Stem Cell Transplant With Post-Transplant Cyclophosphamide	NCT04361058	Leukemia, Myelo... Myelodysplastic... Myelodysplastic...	Nivolumab	18 Years - 65 Years	SCRI Development Innovations, LLC
Nivolumab for High-Risk MDS/AML Patients After Allogeneic Stem Cell Transplant With Post-Transplant Cyclophosphamide	NCT04361058	Leukemia, Myelo... Myelodysplastic... Myelodysplastic...	Nivolumab	18 Years - 65 Years	SCRI Development Innovations, LLC
AB8939 in Patients With Relapsed/Refractory Acute Myeloid Leukemia	NCT05211570	Acute Myeloid L... Acute Myeloid L... Myelodysplastic...	AB8939 Azacitidine	18 Years -	AB Science

Spots Global Cancer Trial Database for myelodysplastic syndrome acute myeloid leukemia