Azacitidine Plus Nivolumab Following Reduced-intensity Allogeneic PBSC Transplantation for Patients With AML and High-risk Myelodysplasia

NCT04128020 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: BTCRC-AML18-342
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a phase I clinical trial that will define the maximum tolerated dose (MTD) and investigate the feasibility and safety of the combination of nivolumab and azacitidine after reduced-intensity allogeneic PBSC transplantation. Dose escalation will follow a traditional 3+3 design. The investigators will first escalate the dose of single agent nivolumab to determine its MTD (if any, at the doses tested), with an expanded cohort at the MTD or highest dose tested. The investigators will then combine escalating azacitidine in combination of with nivolumab at its determined MTD or highest dose tested in earlier cohorts, and expand the highest dose cohort tested with the combination. Patients will be treated according to the dose level cohorts described in the protocol.

Conditions

Aml; AML, Adult

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of nivolumab

  Maximum Tolerated Dose (MTD) of nivolumab

  1 cycle (42 Days)

• Maximum Tolerated Dose (MTD) of nivolumab and azacitidine

  Maximum Tolerated Dose (MTD) of nivolumab and azacitidine

  1 cycle (42 Days)

Secondary Outcomes (9)

• Number of Subjects with Adverse Events

  2 years

• Incidence and severity of acute graft-versus-host disease (GvHD)

  5 years

• Incidence and severity of chronic GvHD

  5 years

• Incidence of infectious complications

  5 years

• Cumulative incidence of relapse

  5 years

Study Arms (2)

Nivolumab

EXPERIMENTAL

Nivolumab: 0.3, 0.5, or 1.0 mg/kg IV, days 1 \& 15

Drug: Nivolumab

Nivolumab + Azacitidine

EXPERIMENTAL

Azacitidine 8,16, 24 mg/m\^2, days 1-5 Nivolumab @MTD (1.0 mg/kg or lower), days 8 \& 15

Drug: Nivolumab; Drug: Azacitidine

Interventions

Nivolumab DRUG

Nivolumab

Also known as: Opdivo

Nivolumab; Nivolumab + Azacitidine

Azacitidine DRUG

Azacitidine

Nivolumab + Azacitidine

Eligibility Criteria

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

You may qualify if:

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Patients must be capable of understanding the investigational nature, potential risks and benefits of the study and provide valid informed consent.
• Age ≥ 60 years at the time of consent who are deemed candidates (by their transplant physician) for reduced-intensity allogeneic PBSC transplantation. A recent randomized trial in patients aged 18-65 years demonstrated that myeloablative conditioning regimens are associated with improved overall survival in AML (largely due to a reduction in the risk of relapse), but resulted in equivalent survival in patients with MDS.4 However, it is acknowledged that some AML patients between 55-65 years may not tolerate myeloablative regimens due to associated comorbidities. Physicians should take the risks of the disease versus the patient's comorbidities in deciding on the appropriate preparative regimen in a given patient.
• Patients aged 18-59 years at the time of consent who are judged not to be candidates for myeloablative allogeneic PBSC transplantation by the transplant physician.
• Karnofsky performance status (KPS) ≥ 70%
• Patients must have any of the following hematological malignancies at the time of transplantation:
• Acute myeloid leukemia (AML) in first (CR1) or subsequent complete remission (CR2, CR3 or beyond), as defined by less than 5% blasts in the bone marrow and peripheral blood.
• Myelodysplastic disorder (MDS) of high or very high-risk according to the revised International Prognostic Scoring System (IPSS-R).1
• Patients with MDS should have the bone marrow and the peripheral blood blast percentage reduced to \<10% within at least 45 days of transplantation.
• The type of cytoreduction therapy used is at the discretion of the treating physician and may include use of hypomethylating drugs but not immune checkpoint inhibitors.
• Therapy-related MDS (regardless of IPSS score)
• Patients must receive a reduced-intensity conditioning (RIC) regimen as defined operationally by the National Marrow Donor Program and CIBMTR. RIC regimens are defined as those containing:
• ≤ 500 cGy total-body irradiation (TBI)
• ≤9 mg/kg total busulfan dose (PO or IV)
• ≤140 mg/m2 total melphalan dose
• ≤10 mg/kg total thiotepa dose

You may not qualify if:

• Use of a myeloablative preparative regimen
• Active central nervous system (CNS) leukemia. Patients with prior CNS leukemia that is now in remission are eligible.
• Prior allogeneic or autologous stem cell transplantation before current transplant
• Use of bone marrow or cord blood as stem cell source
• History of acute GvHD of any grade
• Use of systemic corticosteroids within 28 days prior to registration (except for use as replacement for adrenal insufficiency).
• Uncontrolled bacterial, viral or fungal infection at time of registration (defined as currently taking medication and progression or persistence of clinical symptoms). Patients with prior infection (e.g., fungal infection) that is resolved but need continuing prophylaxis can be included.
• HIV infection or disease at time of transplant. Patients with immune dysfunction are at a significantly higher risk of infection from intensive immunosuppressive therapies. Infectious disease testing will be performed according to local practice.
• Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least three (3) years.
• Patients who have received a live/attenuated vaccine within 30 days of first expected treatment with nivolumab. However, it is recommended that patients who have received an allogeneic transplant should not receive live/attenuated vaccines within two years after allogeneic transplantation.

Sponsors & Collaborators

• Sherif Farag: lead

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Nivolumab; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Lawrence H. Einhorn Professor of Oncology, Indiana University School of Medicine

Study Record Dates

• First Submitted: October 14, 2019
• First Posted: October 16, 2019
• Study Start: October 10, 2019
• Primary Completion: September 28, 2020
• Study Completion: September 28, 2020
• Last Updated: October 12, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share