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Castration Levels of TestosteronePhase 2NCT04159896

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

A Phase 2 study testing Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981 and Nivolumab in people with Castration Levels of Testosterone and Castration-Resistant Prostate Carcinoma, run by Barbara Ann Karmanos Cancer Institute at 2 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older, men only
What is being tested?
Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981 and Nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
2 sitesUnited States
Study dates
13 Nov 2019to 1 Mar 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Men only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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)
  • Progression on a hormonal agent (abiraterone/enzalutamide) and on a chemotherapy agent (docetaxel and/or cabazitaxel) in the metastatic castration resistant setting as per PCWG3 criteria
  • Progression on chemotherapy (e.g. docetaxel, cabazitaxel) in the metastatic castration resistant setting. Progression of disease within 6 months of completing docetaxel in the metastatic castrate-sensitive setting is acceptable
  • Have signed an informed consent document indicating that the subject understands the purpose of and procedures required for the study and are willing to participate in the study
  • Be willing and able to adhere to the prohibitions and restrictions specified in this protocol
  • Willingness to use contraception by a method that is deemed effective by the investigator throughout the treatment period and for at least 30 days following the last dose of therapy
  • Willingness and ability to comply with study procedures and follow-up examination
  • Able to swallow and retain oral medication
  • Willingness and ability to undergo mandatory tumor biopsy at baseline and at the cycle 3 visit
  • Willingness and ability to undergo mandatory whole blood sample collections at baseline, weeks 2-4 in the first cycle, and then monthly

Who cannot join

  • 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)
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  • 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
  • Prior treatment with anti-PD/PD-L1/CTLA4/IDO antibody
  • Untreated brain metastases or spinal cord compression
  • Major surgical procedure or significant traumatic injury within 6 weeks prior to study registration. (> 6 weeks prior to registration is permitted as long as they have fully recovered from any such procedure)
  • History of another primary malignancy except for: malignancy treated with curative intent and no known active disease for >= 5 years, adequately treated non-melanoma skin cancer without evidence of disease, adequately treated carcinoma in situ without evidence of disease
  • Angina, myocardial infarction symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, percutaneous angioplasty or Coronary arterial bypass surgery within the past 3 months
  • The patient has received any investigational drug within 28 days prior to registration or 5 half-lives of the investigational drug, whichever is sooner

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • University of Michigan Comprehensive Cancer Center

    Ann Arbor, Michigan, 48109

  • Wayne State University/Karmanos Cancer Institute

    Detroit, Michigan, 48201

Other trials in United States

About this study

Official title: Phase II Multi-Center Trial of ESK981 in Combination With Nivolumab in Patients With Metastatic Castrate Resistant Prostate Cancer

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the prostate specific antigen (PSA) >= 50% response rate (PSA50) from baseline using the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981) plus nivolumab in men with metastatic castration resistant prostate cancer (mCRPC) who have progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor) and chemotherapy (docetaxel and/or cabazitaxel).

II. To assess the safety and tolerability of ESK981 plus nivolumab.

SECONDARY OBJECTIVES:

  1. To determine the time to PSA response (TTPR) in patients with mCRPC. II. To determine the duration of PSA response (PRD) in patients with mCRPC. III. To determine PSA progression rates as defined by the PCWG3 criteria. IV. To determine PSA progression free survival (PPFS) as defined by the PCWG3 criteria.

CORRELATIVE/EXPLORATORY/TERTIARY OBJECTIVE:

  1. To assess exploratory biomarkers from blood and tumor biopsies.

OUTLINE:

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

After completion of study treatment, patients are followed up every 3 months for 5 years.

Being tested
Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981, Nivolumab
Medical subject headings
Prostatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981Drug

    Also called 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

    Given PO

  • NivolumabBiological

    Also called 946414-94-4, BMS-936558, MDX-1106, NIVO

    Given IV

Study groups in NCT04159896
Study groupRoleWhat they receive
Treatment (ESK981, nivolumab)ExperimentalPatients 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.
Receives: Drug: Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981; Biological: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: From treatment administration up to a maximum duration of 27 months

Secondary outcomes (3)

  1. Time to PSA Response (TTPR)

    Descriptive statistics of TTPR will be used to summarize the time to PSA response. These descriptives will include N, median, mean, standard deviation (SD), interquartile range (IQR), minimum, and maximum.

    Measured: From treatment administration up to a maximum duration of 27 months

  2. Duration of PSA Response (PRD)

    The censored distributions will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life table, each one with its respective 80% CI.

    Measured: From treatment administration up to a maximum duration of 27 months

  3. Overall Survival (OS)

    Time from start of treatment to death due to any cause.

    Measured: From treatment administration up to a maximum duration of 27 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Nov 2019
  2. Study start13 Nov 2019
  3. Primary completion1 Mar 2022
  4. Study completion1 Mar 2022

Why it stopped: The study was closed to accrual on 3/1/21 due to safety concerns since 2 patients experienced CVA events.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04159896
Sponsor's protocol ID
2019-031
Other IDs
P30CA022453
Status last verified
Jul 2024
First submitted
21 Oct 2019
Last updated
16 Jul 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 39503807

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pan-VEGFR/TIE2 Tyrosine Kinase Inhibitor CEP-11981 and Nivolumab in people with Castration Levels of Testosterone and Castration-Resistant Prostate Carcinoma, run by Barbara Ann Karmanos Cancer Institute at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 16 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Prostate Specific Antigen (PSA) >= 50% Response Rate (PSA50) (time frame: From treatment administration up to a maximum duration of 27 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04159896, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jul 2024.

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