Clinical Trials /

To Evaluate Safety and Tolerability of VERU-111 in Men With Advanced Metastatic Castration Resistant Prostate Cancer

NCT03752099

Description:

Phase 1b - To assess the safety/tolerability of VERU-111 and to determine the maximum tolerated dose of VERU-111 in patients with metastatic, castration resistant prostate cancer who have failed a novel androgen blocking agent therapy (mCRPC). Phase 2 - To estimate the PSA50 response rate, defined as a decline in PSA to ≥50% of baseline level, confirmed with a second measurement at least 3 weeks apart (PCWG3).

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: To Evaluate Safety and Tolerability of VERU-111 in Men With Advanced Metastatic Castration Resistant Prostate Cancer
  • Official Title: A Phase 1b/2 Study to Evaluate the Safety and Tolerability of VERU-111 in Men With Advanced Metastatic Castration Resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: V1011101
  • NCT ID: NCT03752099

Conditions

  • Metastatic Castration Resistant Prostate Cancer

Interventions

DrugSynonymsArms
VERU-111BisindoleVERU-111 4.5mg

Purpose

Phase 1b - To assess the safety/tolerability of VERU-111 and to determine the maximum tolerated dose of VERU-111 in patients with metastatic, castration resistant prostate cancer who have failed a novel androgen blocking agent therapy (mCRPC). Phase 2 - To estimate the PSA50 response rate, defined as a decline in PSA to ≥50% of baseline level, confirmed with a second measurement at least 3 weeks apart (PCWG3).

Detailed Description

      Up to 7 sites in the US only with approximately 18 patients for Phase 1b portion (3 patients
      per dose group) of the study. Additional patients may be enrolled into the Phase 1b portion
      of the study depending on the safety and tolerability assessment in the dose escalation
      scheme.

      Approximately 26 patients will be enrolled in the Phase 2 portion of the study

      Phase 1b Approximately 18 patients for Phase 1b portion (3 patients per dose group) will be
      enrolled into the study. Additional subjects may be enrolled based on the assessment of
      safety and tolerability in the dose escalation scheme.

      VERU-111 will be administered orally for three 21-day cycles in which the patient will take
      the study drug (capsules) daily with food for 7 days and then have a 14-day treatment free
      period.

      Dose Escalation Criteria In Phase 1b, three patients will be planned at each dose level and
      followed for one 21-day cycle.

        -  If 0/3 patients exhibit a dose limiting toxicity (DLT) after one 21-day cycle, the next
           patient will be treated at the next dose level.

        -  If one patient out of the 3 exhibits a DLT related to the study agent, the cohort will
           be expanded to up to 6 patients. If 1 of 6 patients exhibits a DLT related to the study
           agent, then the next patient will enroll at the next dose level.

        -  If 2 of the first 3 subjects OR 2 of the first 6 patients exhibit a DLT related to the
           study agent, the MTD is considered to have been determined and at least 3 additional
           patients will be entered at the dose level below the one at which DLT is observed. Dose
           escalations will occur no sooner than 3 weeks after the last patient on the dose level
           has begun therapy to allow for full assessment of DLT. No intra-patient escalation will
           be allowed.

        -  If <1 of 6 patients experience a DLT, this will be the recommended Phase 2 dose for the
           expansion cohorts.

      A Cohort Review Committee, consisting of investigators, the medical monitor and the sponsor,
      will monitor the trial on an ongoing basis for safety and will guide dose escalation
      decisions based on the occurrence of DLTs as described in this protocol.

      The planned dosing for VERU-111 in the Phase 1b portion will be:

      Treatment Group Daily dose Dosing Regimen

        1. 4.5mg Daily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue
           past the planned three 21-day cycles until DLT or disease progression is observed.

        2. 9mg Daily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue
           past the planned three 21-day cycles until DLT or disease progression is observed.

        3. 18mg Daily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue
           past the planned three 21-day cycles until DLT or disease progression is observed.

        4. 27mg Daily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue
           past the planned three 21-day cycles until DLT or disease progression is observed.

        5. 36mg Daily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue
           past the planned three 21-day cycles until DLT or disease progression is observed.

        6. 45mg1 Daily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue
           past the planned three 21-day cycles until DLT or disease progression is
           observed.Treatment may continue past the planned three 21-day cycles until DLT or
           disease progression is observed.

      1 If after the first 21-day cycle for the 45 mg in Treatment Group 5 no DLT is observed, then
      additional dose levels and additional dosing schedules (i.e. 14 days of daily dosing followed
      by a 7-day treatment free period) may be considered.

      Phase 2 The maximum tolerated dose of VERU-111 identified in the Phase 1b portion of the
      study will be used in the Phase 2 portion of the study. The dosing regimen will be daily
      dosing for 7 days followed by a 14-day treatment free period (21-day cycle). Three 21-day
      cycles are planned in this study. However, treatment may continue past the planned three
      21-day cycles until DLT or disease progression is observed.
    

Trial Arms

NameTypeDescriptionInterventions
VERU-111 4.5mgExperimentalDaily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue past the planned three 21-day cycles until DLT or disease progression is observed.
  • VERU-111
VERU-111 9mgExperimentalDaily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue past the planned three 21-day cycles until DLT or disease progression is observed.
  • VERU-111
VERU-111 18mgExperimentalDaily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue past the planned three 21-day cycles until DLT or disease progression is observed.
  • VERU-111
VERU-111 27mgExperimentalDaily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue past the planned three 21-day cycles until DLT or disease progression is observed.
  • VERU-111
VERU-111 36mgExperimentalDaily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue past the planned three 21-day cycles until DLT or disease progression is observed.
  • VERU-111
VERU-111 45mgExperimentalDaily dosing on Day 1-7 of each 21-day cycle for 3 cycles Treatment may continue past the planned three 21-day cycles until DLT or disease progression is observed.
  • VERU-111

Eligibility Criteria

        Inclusion Criteria:

        To be included in this study, patients should meet all of the following criteria:

        • Willing and able to provide written informed consent and HIPAA authorization for the
        release of personal health information.

        NOTE: HIPAA authorization may be either included in the informed consent or obtained
        separately.

          -  Patients >18 years of age.

          -  Histological or cytologic proof of adenocarcinoma of the prostate.

          -  Radiographic evidence of metastatic disease by CT scan or MRI and/or bone scan.

          -  Known castration resistant prostate cancer, defined according to PCWG3 criteria.

          -  Subjects who have metastatic castration resistant prostate cancer that have maintained
             ADT and have failed a novel androgen receptor agent (abiraterone or enzalutamide)
             defined as:

               -  Serum PSA progression of two consecutive increases in PSA over a previous
                  reference value within 6 months of first study treatment, each measurement at
                  least two weeks apart.

        Or

          -  Documented bone lesions by the appearance of two or more new lesions on bone
             scintigraphy or dimensionally-measurable soft tissue metastatic lesion assessed by CT
             or MRI.

               -  Absolute PSA ≥2.0 ng/ml at screening.

               -  Prior chemotherapy for mCRPC:

          -  Phase 1b - ONE prior taxane chemotherapy for mCRPC will be allowed during the Phase 1b
             portion of study as long as the last dose was more than four weeks prior to the first
             dose of study drug.

          -  Phase 2 - Prior chemotherapy for mCRPC is not allowed in the Phase 2 portion of the
             study. Prior chemotherapy for metastatic hormone sensitive prostate cancer will not
             qualify as a prior chemotherapy and the last dose must be >6 months prior to
             enrollment.

               -  Prior treatment with abiraterone, enzalutamide, bicalutamide, and/or ketoconazole
                  is allowed. There is no limit on the maximum number or types of prior hormonal
                  therapies received. The patients should be off prior therapy for at least two
                  weeks (4 weeks off bicalutamide or nilutamide treatment) prior to first dose of
                  study drug.

               -  ECOG performance status ≤2.

               -  Participants must have normal organ and bone marrow function measured within 28
                  days prior to administration of study treatment as defined below:

          -  Hemoglobin 9.0 g/dL with no blood transfusion in the past 28 days.

          -  Absolute neutrophil count (ANC) 1.5 x 109/L.

          -  Platelet count 100 x 109/L.

          -  Total bilirubin ≤1.5 x institutional upper limit of normal (ULN) (or <2.5 x ULN for
             patients with known Gilberts disease).

          -  Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase
             (SGOT))/Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT))
             ≤2.5 x institutional upper limit of normal.

        Note: Patients with elevations in bilirubin, AST, or ALT should be thoroughly evaluated for
        the etiology of this abnormality prior to entry and patients with evidence of viral
        infection should be excluded.

          -  Participants must have a life expectancy >3 months.

          -  Male participants, and their partners, who are sexually active and of childbearing
             potential, must agree to the use of two highly effective forms of contraception in
             combination [see Appendix E for acceptable methods], throughout the period of taking
             study treatment and for at least 4 weeks after the last dose of VERU-111 to prevent
             pregnancy in a partner.

          -  Other than the metastatic prostate cancer, no evidence (within 5 years) of prior
             malignancies (except successfully treated basal cell or squamous cell carcinoma of the
             skin or other cancers treated with curative intent >3 years prior).

          -  Participants must agree to either refrain from prolonged exposure to the sun or agree
             to use at least SPF 50 on all exposed skin and protective clothing during prolonged
             sun exposure throughout participation in this study and/or treatment with VERU-111.

        Exclusion Criteria:

        Patients that meet any of the criteria listed below will not be eligible for study entry:

          -  Histologic identification of small cell carcinoma of the prostate or neuroendocrine
             pathology in either biopsy or prostatectomy tissue.

          -  Has received external-beam radiotherapy within the last 2 weeks prior to start of
             study treatment.

          -  Patients receiving full dose anticoagulation therapy are not eligible for study.

          -  Patients with prior history of a thromboembolic event within the last 6 months.

          -  Participation in another clinical study with an investigational product during the
             last 4 weeks/28 days.

          -  Patients should be excluded if they have had prior systemic treatment with two prior
             taxane chemotherapies for advanced prostate cancer. No limit to other prior therapies.

          -  Concurrent use of other anticancer agents (see Appendix G) or treatments, with the
             following exceptions:

             o Ongoing treatment with denosumab (Prolia) or bisphosphonate (e.g., zoledronic acid)
             is allowed. Ongoing treatment should be kept at a stable schedule; however, if
             medically required, a change of dose, compound, or both is allowed.

          -  Any treatment modalities involving major surgery within 4 weeks prior to the start of
             study treatment.

          -  Patients are excluded if they have active known brain metastases or leptomeningeal
             metastases.

          -  Patients should be excluded if they have a positive test for hepatitis B virus surface
             antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating
             acute or chronic infection.

          -  History of severe hypersensitivity reaction to any taxane chemotherapy.

          -  Has imminent or established spinal cord compression based on clinical findings and/or
             MRI.

          -  Any other serious illness or medical condition that would, in the opinion of the
             investigator, make this protocol unreasonably hazardous.

          -  Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
             caused by previous cancer therapy, excluding alopecia.

          -  Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant
             systemic disease or active, uncontrolled infection. Examples include, but are not
             limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial
             infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung
             disease, or any psychiatric disorder that prohibits obtaining informed consent.

          -  Total bilirubin levels > ULN or OR AST/ALT levels >1.5xULN with WITH concomitant
             alkaline phosphatase levels >2.5xULN.

        The following exclusion criterion is added to the Phase 1b portion of the study only:

        • Patients with substantial visceral disease who require immediate treatment with cytotoxic
        therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:21 Days
Safety Issue:
Description:Patients will be assessed for toxicities at each clinical evaluation. Toxicities will be graded according to CTCAE v5.0 standardized grading scales. The incidence of grade 3-5 toxicities will be reported.Toxicities will be reported as a tabulated table by type and grade.

Secondary Outcome Measures

Measure:PSA progression-free survival
Time Frame:63 Days
Safety Issue:
Description:PSA progression per PCWG3 will be used. PSA-PFS will be defined as an increase in 25% over a nadir value, confirmed by a follow-up PSA at least 3 weeks later. If patients are removed from study prior to PSA progression, then they will be censored at that time. We will use the Kaplan-Meier method to summarize the median PSA-PFS.
Measure:Progression-free survival
Time Frame:63 days
Safety Issue:
Description:Measured from the time of first dose to objective clinical or radiographic tumor progression as defined by PCWG3 for progressive disease or death and summarized using a Kaplan-Meier curve. The time to progression will be the earliest observed time of progression. Patients whose disease has not progressed at follow-up will either be censored at the date of follow-up or if they continue therapy after the planned 3 cycles, they will be followed for progression. A Kaplan-Meier method will be used to summarize the median PFS.
Measure:Percentage of Patients who achieve Objective Response Rate
Time Frame:63 Days
Safety Issue:
Description:Percentage of patients who achieve an objective response by RECIST1.1 criteria (i.e. Complete response or Partial Response) to VERU-111. The objective response rate and the exact 95% confidence interval will be estimated for the population of patients with RECIST evaluable disease.
Measure:Number of participants with treatment related adverse events (Safety and Tolerability)
Time Frame:91 Days
Safety Issue:
Description:Standard safety summaries will be provided for treatment exposure, patient disposition, adverse events leading to discontinuation, serious adverse events, and all events resulting in death, including those up to 28 days after treatment discontinuation. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance using CTCAE v5.0 grade ≥3 toxicities experienced by patients on the trial.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Veru Inc.

Last Updated

November 6, 2019