OX40, Venetoclax, Avelumab, Glasdegib, Gemtuzumab Ozogamicin, and Azacitidine in Relapsed or Refractory Acute Myeloid Leukemia

NCT03390296 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 2017-0337NCI-2018-00972
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

This phase Ib/II trial studies the side effects and best dose of anti-OX40 antibody PF-04518600 (OX40) and how well it works alone or in combination with venetoclax, avelumab, glasdegib, gemtuzumab ozogamicin, and azacitidine in treating patients with acute myeloid leukemia that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as OX40, avelumab, and gemtuzumab ozogamicin, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Glasdegib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as venetoclax and azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving OX40, venetoclax, avelumab, glasdegib, gemtuzumab ozogamicin, and azacitidine may work better in treating patients with acute myeloid leukemia.

Conditions

Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Number of Participants With a Response

  Response is: CR + complete response with incomplete recovery of platelets (CRp) + complete response with incomplete recovery of counts (CRi) within 3 months. CR: Bone Marrow blasts \</= 5%, Absolute neutrophil count \>/= 1,000, Platelets \>/= 100 and no extra medullary disease.CRp: Bone Marrow blasts \</= 5%, Absolute neutrophil count \>/= 1,000 and no extra medullary disease. CRi: Bone Marrow blasts \</= 5%

  within 3 months of initiation of therapy

Secondary Outcomes (1)

• Overall Survival

  Up to 4 years

Study Arms (6)

Arm A (anti-OX40 antibody PF-04518600)

EXPERIMENTAL

Patients receive anti-OX40 antibody PF-04518600 IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Biological: Anti-OX40 Agonist Monoclonal Antibody PF-04518600

Arm B (azacitidine, venetoclax, GO)

EXPERIMENTAL

Patients receive azacitidine IV over 10-40 minutes or via injection SC on days 1-7 or 1-5 and 8-9. Patients also receive venetoclax PO on days 1-28 and GO IV over 2 hours on day 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine; Drug: Gemtuzumab Ozogamicin; Drug: Venetoclax

Arm C (azacitidine, GO, avelumab)

EXPERIMENTAL

Patients receive azacitidine and GO as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Avelumab; Drug: Gemtuzumab Ozogamicin; Drug: Azacitidine

Arm D (azacitidine, venetoclax, avelumab)

EXPERIMENTAL

Patients receive azacitidine and venetoclax as in Arm A and avelumab as in Arm C. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Avelumab; Drug: Azacitidine; Drug: Venetoclax

Arm E (azacitidine, avelumab, anti-OX40 antibody PF-04518600)

EXPERIMENTAL

Patients receive azacitidine and avelumab as in Arm C and anti-OX40 antibody PF-04518600 as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Biological: Anti-OX40 Agonist Monoclonal Antibody PF-04518600; Drug: Avelumab; Drug: Azacitidine

Arm F (GO, glasdegib)

EXPERIMENTAL

Patients receive GO IV over 2 hours on days 1, 4, and 7, and glasdegib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Gemtuzumab Ozogamicin; Drug: Glasdegib; Drug: Glasdegib Maleate

Interventions

Anti-OX40 Agonist Monoclonal Antibody PF-04518600 BIOLOGICAL

Given IV

Also known as: PF-04518600, PF04518600

Arm A (anti-OX40 antibody PF-04518600); Arm E (azacitidine, avelumab, anti-OX40 antibody PF-04518600)

Avelumab DRUG

Given IV

Also known as: Bavencio, MSB-0010718C, MSB0010718C

Arm C (azacitidine, GO, avelumab); Arm D (azacitidine, venetoclax, avelumab); Arm E (azacitidine, avelumab, anti-OX40 antibody PF-04518600)

Azacitidine DRUG

Given IV or SC

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Arm B (azacitidine, venetoclax, GO); Arm D (azacitidine, venetoclax, avelumab); Arm E (azacitidine, avelumab, anti-OX40 antibody PF-04518600)

Gemtuzumab Ozogamicin DRUG

Given IV

Also known as: Calicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody, CDP-771, CMA-676, gemtuzumab, hP67.6-Calicheamicin, Mylotarg, WAY-CMA-676

Arm B (azacitidine, venetoclax, GO); Arm C (azacitidine, GO, avelumab); Arm F (GO, glasdegib)

Glasdegib DRUG

Given PO

Also known as: PF 04449913, PF-04449913, PF04449913

Arm F (GO, glasdegib)

Glasdegib Maleate DRUG

Given PO

Also known as: Daurismo, PF 04449913 Maleate

Arm F (GO, glasdegib)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Arm B (azacitidine, venetoclax, GO); Arm D (azacitidine, venetoclax, avelumab)

Eligibility Criteria

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

You may qualify if:

• ARMS A-G: RR AML: Patients with AML who are refractory or relapsed (any salvage) with no available therapies or not candidates for available therapies. For patients with prior MDS or chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN) who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for AML with the exception of MDS or CMML treated with hypomethylating agents (HMAs). Patients with MDS or CMML treated with HMA therapies who progress to AML, and have no available therapies or are not candidates for available therapies, will be eligible at the time of progression to AML.
• Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is permitted.
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2.
• Total bilirubin =\< 2.0 times upper limit of normal (x ULN).
• Aspartate aminotransferase or alanine aminotransferase =\< 2.5 x ULN (aspartate aminotransferase or alanine aminotransferase =\< 5.0 x ULN if deemed related to leukemia by the treating physician).
• Adequate renal function defined by an estimated creatinine clearance \>= 40 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
• Patients must provide written informed consent.
• In the absence of rapidly progressive disease, the interval from prior treatment to the time of initiation of protocol therapy will be at least 14 days for prior anti-leukemic therapy, with the exception of hydroxyurea as noted below, OR at least 5 half-lives for cytotoxic/noncytotoxic agents, whichever is shorter. The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochure's, or drug-administration manuals) and will be documented in the protocol eligibility document. The toxicity from prior therapy should have resolved to grade =\< 1, however alopecia and sensory neuropathy grade =\< 2 not constituting a safety risk based on investigators judgement is acceptable. Since the effect of most IO-agents, HMA-therapies, SMO-inhibitors, venetoclax may be delayed, use of hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and will not require a washout.
• Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted. Patients with a known history of CNS disease or leukemic brain metastasis must have been treated locally, have at least 3 consecutive lumbar punctures (LPs) with no evidence of CNS leukemia, and must be clinically stable for at least 4 weeks prior to enrollment and have no ongoing neurological symptoms that in the opinion of the treating physician are related to the CNS disease (sequelae that are a consequence of the treatment of the CNS disease are acceptable).
• Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment.
• Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment. Adequate methods of contraception include:
• Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
• Combination of any of the two following:

You may not qualify if:

• Patients with a known allergy or hypersensitivity to the protocol therapies or any of their components to be used in the arm the patient is to be enrolled on. Known severe hypersensitivity reactions to monoclonal antibodies (grade \>= 3 National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\] 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
• Patients with a known history of severe interstitial lung disease or severe pneumonitis or active pneumonitis/pneumonia or pulmonary pathology that is not well controlled in the opinion of the treating physician and/or principal investigator (PI).
• Clinically significant (i.e., active) cardiovascular disease: acute cerebral vascular accident/stroke (\< 6 months prior to enrollment) excluding transient ischemic attack (TIA), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (\>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication.
• Ejection fraction \< 50% on screening echocardiography (ECHO) or multigated acquisition scan (MUGA).
• Persisting toxicity related to prior therapy of grade \> 1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy grade =\< 2 is acceptable.
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: \* Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
• Current use of immunosuppressive medication, EXCEPT for the following:
• Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
• Systemic corticosteroids at physiologic doses =\< 10 mg/day of prednisone or equivalent;
• Steroids as premedication for hypersensitivity reactions (e.g., computed tomography \[CT\] scan premedication).
• Prior organ transplantation including allogenic stem-cell transplantation within 3 months prior to planned enrollment.
• Patients with symptomatic CNS leukemia or patients with poorly controlled CNS leukemia.
• Active and uncontrolled disease (active infection requiring systemic therapy, fever likely secondary to infection within prior 48 hours, uncontrolled hypertension despite adequate medical therapy as judged by the treating physician.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
• Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Short NJ, Borthakur G, Pemmaraju N, Dinardo CD, Kadia TM, Jabbour E, Konopleva M, Macaron W, Ning J, Ma J, Pierce S, Alvarado Y, Sasaki K, Takahashi K, Estrov Z, Masarova L, Issa GC, Montalban-Bravo G, Andreeff M, Burger JA, Miller D, Alexander L, Naing A, Garcia-Manero G, Ravandi F, Daver N. A multi-arm phase Ib/II study designed for rapid, parallel evaluation of novel immunotherapy combinations in relapsed/refractory acute myeloid leukemia. Leuk Lymphoma. 2022 Sep;63(9):2161-2170. doi: 10.1080/10428194.2022.2062345. Epub 2022 Apr 20.

  PMID: 35442137 DERIVED

Related Links

• MD Anderson Cancer Center Website

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

avelumab; Azacitidine; Gemtuzumab; glasdegib; venetoclax

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Naval Daver MD./Associate Professor
• Organization: The University of Texas MD Anderson Cancer Center

NDaver@mdanderson.org

713-794-4392

Study Officials

• Naval G Daver

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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: December 28, 2017
• First Posted: January 4, 2018
• Study Start: December 27, 2017
• Primary Completion: February 4, 2022
• Study Completion: February 4, 2022
• Last Updated: September 5, 2023
• Results First Posted: May 24, 2023

Record last verified: 2023-08

Locations

US (1)