ESK981 and Nivolumab for the Treatment of Metastatic Castration Resistant Prostate Cancer

NCT04159896 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 2019-031P30CA022453
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

Brief Summary

This phase II trial studies the side effects of ESK981 and nivolumab and to see how well they work for the treatment of castration resistant prostate cancer that has spread to other places in the body (metastatic). ESK981 is an investigational drug that targets several important pathways that are believed to play a role in the spread of cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to see if giving ESK981 and nivolumab together works better in treating metastatic castration resistant prostate cancer compared to usual treatments.

Conditions

Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Prostate Carcinoma Metastatic in the Bone; Stage IVB Prostate Cancer AJCC v8

Outcome Measures

Primary Outcomes (1)

• Prostate Specific Antigen (PSA) >= 50% Response Rate (PSA50)

  Will assess PSA decline of \>= 50% from baseline (PSA50), using the Prostate Cancer Working Group 3 (PCWG3) criteria. Two-sided Wilson type 95% confidence interval (CI) estimates will be calculated.

  From treatment administration up to a maximum duration of 27 months

Secondary Outcomes (3)

• Time to PSA Response (TTPR)

  From treatment administration up to a maximum duration of 27 months

• Duration of PSA Response (PRD)

  From treatment administration up to a maximum duration of 27 months

• Overall Survival (OS)

  From treatment administration up to a maximum duration of 27 months

Other Outcomes (6)

• Somatic and Germline Mutations

  From treatment administration up to a maximum duration of 27 months

• ETS/Kinase Gene Fusions

  From treatment administration up to a maximum duration of 27 months

• Androgen Receptor (AR) Signaling

  From treatment administration up to a maximum duration of 27 months

Study Arms (1)

Treatment (ESK981, nivolumab)

EXPERIMENTAL

Patients receive ESK981 PO QD for 5 consecutive days per week, followed by a 2-day break. Patients also receive nivolumab IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981; Biological: Nivolumab

Interventions

Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981 DRUG

Given PO

Also known as: 4H-Indazolo(5,4-a)pyrrolo(3,4-C)carbazol-4-one, 2,5,6,11,12,13-Hexahydro-2-methyl-11-(2-methylpropyl)-8-(2-pyrimidinylamino), 856691-93-5, BOL-303213X, CEP 11981, ESK981

Treatment (ESK981, nivolumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: 946414-94-4, BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Treatment (ESK981, nivolumab)

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: It is a prostate cancer research
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eastern Cooperative Group (ECOG) performance status =\< 1
• Recovery to baseline or =\< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically non-significant and/or stable on supportive therapy
• Absolute neutrophil count (ANC) \>= 1.5 K/mm\^3
• Hemoglobin (Hgb) \>= 9 g/dL
• Platelets (Plt) \>= 100,000/mm\^3
• Serum creatinine =\< 1.5 times the upper limit of normal OR creatinine clearance \> 30 mL/min by Cockcroft-Gault formula
• Total bilirubin =\< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) =\< 2.5 x ULN (=\< 5 x ULN with known hepatic metastases)
• Alanine aminotransferase (ALT) =\< 2.5 x ULN (=\< 5 x ULN with known hepatic metastases)
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels =\< 1.5 x ULN (If patient is receiving anticoagulation that is expected to alter these levels, should be in targeted therapeutic range for that agent)
• Patient must have progressive disease while receiving androgen deprivation therapy (ADT) defined by any one of the following as per the PCWG3 criteria for PSA, measurable or non-measurable (bone) disease and must have a castrate serum testosterone level (i.e. =\< 50 ng/dL) at screening:
• PSA: At least two consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, with the final value \>= 2.0 ng/mL
• Measurable disease (by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1): \>= 20% increase (with an absolute increase of at least 5 mm) in the sum of diameters of all measurable lesions or the development of one or more new lesions. The short axis of a target lymph node must be more than 15 mm to be assessed for change in size
• Non-measurable (bone) disease: The appearance of two or more new areas of uptake on bone scan consistent with metastatic disease compared to previous imaging during castration therapy. The increased uptake of pre-existing lesions on bone scan will not be taken to constitute progression, and ambiguous results must be confirmed by other imaging modalities (e.g. X-ray, computed tomography \[CT\] or magnetic resonance imaging \[MRI\])
• Metastatic prostate cancer (M1) as documented by appropriate medical imaging (i.e. CT-Scan, positron emission tomography \[PET\] scan or bone scan)

You may not qualify if:

• Systemic therapy (other than a gonadotrophin releasing hormone \[GnRH\] agonist/antagonist) for CRPC within the past two weeks from cycle 1/day 1 including:
• CYP-17 inhibitors (e.g. ketoconazole, abiraterone)
• Antiandrogens (e.g. bicalutamide, nilutamide)
• Second generation antiandrogens (e.g. enzalutamide, ARN-509, galeterone)
• Immunotherapy (e.g. sipuleucel-T, ipilimumab)
• Chemotherapy (e.g. docetaxel, cabazitaxel)
• Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153, etc.) within the past year
• Have any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements
• The patient is currently on warfarin or heparin therapy
• The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria or gastrointestinal bleeding
• The patient has a history of a clinically significant cardiovascular or cerebrovascular event within 3 months prior to study entry
• The patient has uncontrolled hypertension defined as a blood pressure measurement greater than 150 mm Hg systolic or 90 mm Hg diastolic with medication
• The patient has previously been enrolled in the study or received ESK981
• The patient has known hypersensitivity to gelatin or lactose monohydrate
• The patient has taken a medication known to be a potent inducer of CYP1A2, CYP2C8, or CYP3A4 within 4 weeks prior to the first dose of study drug

Sponsors & Collaborators

• Barbara Ann Karmanos Cancer Institute: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Related Publications (1)

• Heath EI, Chen W, Choi JE, Dobson K, Smith M, Maj T, Kryczek I, Zou W, Chinnaiyan AM, Qiao Y. Phase II trial of multi-tyrosine kinase inhibitor ESK981 in combination with PD-1 inhibitor nivolumab in patients with metastatic castration-resistant prostate cancer. Invest New Drugs. 2024 Dec;42(6):675-684. doi: 10.1007/s10637-024-01482-8. Epub 2024 Nov 6.

  PMID: 39503807 DERIVED

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo(5,4-a)pyrrolo(3,4-c)carbazol-4-one; Nivolumab

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

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

Limitations and Caveats

Early termination leading to small numbers of subjects analyzed.

Results Point of Contact

• Title: Dr. Elisabeth Heath
• Organization: Karmanos Cancer Institute

heathe@karmanos.org

313.576.8734

Study Officials

• Elisabeth Heath, M.D.

  Barbara Ann Karmanos Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 21, 2019
• First Posted: November 12, 2019
• Study Start: November 13, 2019
• Primary Completion: March 1, 2022
• Study Completion: March 1, 2022
• Last Updated: July 16, 2024
• Results First Posted: July 16, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)