Clinical Trials /

Study of ORIC-101 in Combination With Enzalutamide

NCT04033328

Description:

The purpose of this study is to establish the recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of ORIC-101 in combination with enzalutamide (Xtandi®) when administered to patients with metastatic prostate cancer progressing on enzalutamide.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of ORIC-101 in Combination With Enzalutamide
  • Official Title: An Open-Label Phase 1b Study of ORIC-101 in Combination With Enzalutamide in Patients With Metastatic Prostate Cancer Progressing on Enzalutamide

Clinical Trial IDs

  • ORG STUDY ID: ORIC-101-02
  • NCT ID: NCT04033328

Conditions

  • Prostatic Neoplasms

Interventions

DrugSynonymsArms
ORIC-101Dose Escalation
enzalutamide 40 MG oral capsule [Xtandi]Dose Escalation

Purpose

The purpose of this study is to establish the recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of ORIC-101 in combination with enzalutamide (Xtandi®) when administered to patients with metastatic prostate cancer progressing on enzalutamide.

Detailed Description

      ORIC-101 is a small molecule GR antagonist being developed for the treatment of patients with
      solid tumor malignancies. Mechanistically, ORIC-101 inhibits GR transcriptional activity and
      blocks the pro-survival signals mediated by the activated nuclear receptor.

      This is an open-label, single arm, multicenter, dose escalation followed by dose expansion
      study to assess the safety and preliminary antitumor activity of ORIC-101 in combination with
      enzalutamide in patients progressing on enzalutamide. Patients deemed eligible will receive
      treatment with ORIC-101 in addition to continuing their current enzalutamide therapy.

      Escalating dose levels of ORIC-101 will be administered orally, once daily in combination
      with enzalutamide 160 mg. Parallel enrollment for assessment of PK/PD modulation in up to 3
      additional patients presenting with tumors expressing high levels of GR (GR-high) may be
      performed at each dose level after the dose level has cleared the initial dose-limiting
      toxicity evaluation period; these additional patients may serve as supplemental patients for
      selection of the maximum tolerated dose and/or RP2D.

      Dose expansion will further evaluate the safety and preliminary antitumor activity of
      ORIC-101 in patients presenting with different levels of GR expressing-tumors.
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalORIC-101 dosed orally, once per day in combination with enzalutamide (160 mg) of each 28-day cycle.
  • ORIC-101
  • enzalutamide 40 MG oral capsule [Xtandi]
Dose ExpansionExperimentalRP2D dose
  • ORIC-101
  • enzalutamide 40 MG oral capsule [Xtandi]

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed adenocarcinoma of the prostate

          -  Metastatic prostate cancer currently being treated with enzalutamide (Xtandi®) 160 mg
             once daily plus surgical or ongoing chemical castration, with baseline testosterone
             level <50 ng/dL

          -  Must have been on treatment with enzalutamide for at least 3 months prior to
             documented evidence of PSA progression defined as per PCWG3: minimum of 2 rising
             values (3 measurements) obtained a minimum of one week apart with the latest result
             being at least 2.0 ng/mL (or 1.0 ng/mL if PSA rise is the only indication of
             progression)

          -  Agreement and ability to undergo on-study core biopsies, as follows, through a
             procedure that is deemed to be clinically feasible and not carry significant risk:

               -  one pre-treatment tumor biopsy obtained while on treatment with enzalutamide
                  prior to enrollment on this study; and

               -  one post-treatment tumor biopsy during Cycle 2;

               -  one end of treatment tumor biopsy (optional)

          -  ECOG performance status 0 or 1

          -  Life expectancy of at least 3 months

          -  Adequate organ function as defined by the following criteria:

               -  ANC ≥1500 cells/mm3 (1.5 × 103 cells/mm3)

               -  Platelets ≥100,000 /µL (100 × 109 /L)

               -  Hemoglobin ≥9.0 g/dL (90 g/L)

               -  AST (SGOT) or ALT (SGPT) ≤2.5 × ULN, ≤5.0 × ULN for patients with liver
                  metastases

               -  Bilirubin ≤1.5 × ULN; patients with a known history of Gilbert's syndrome and/or
                  isolated elevations of indirect bilirubin are eligible

               -  QTcF ≤450 msec, ≤480 msec for patients with bundle branch block (BBB)

          -  Capable of giving signed informed consent

        Exclusion Criteria:

          -  No intervening therapy between enzalutamide treatment and enrollment on this study

          -  Any other active malignancy, with the exception of adequately treated non-melanoma
             skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 solid tumor
             malignancies without evidence of disease, or other solid tumors curatively treated
             with no evidence of disease for ≥5 years from enrollment

          -  Current treatment on another therapeutic clinical trial

          -  Prior or current treatment with ORIC-101 or any other GR antagonist (eg, CORT-125281,
             mifepristone, relacorilant)

          -  Prior chemotherapy in the metastatic castration-resistant prostate cancer setting

          -  Prior treatment with a second-generation AR modulator (eg, apalutamide, abiraterone,
             darolutamide)

          -  History of Cushing's syndrome or adrenal insufficiency

          -  History or presence of CNS metastases

          -  History of seizures or condition that may predispose to seizures

          -  Current (at C1D1) or requirement for chronic use of systemic corticosteroids with the
             exception of inhaled, topical, intraocular, intranasal, or intraarticular
             corticosteroids

          -  Current (within 10 days prior to first dose of ORIC-101) or expected on-study
             treatment with specified strong CYP3A4 inhibitors or inducers

          -  Receiving any other anticancer therapy, including radiotherapy within 21 days prior to
             C1D1. Patients must have recovered from all toxicities from prior anticancer therapies
             and/or radiotherapy

          -  Major surgery within 21 days prior to C1D1 or incomplete recovery from adverse effects
             resulting from such procedure

          -  Known human immunodeficiency virus (HIV) infection

          -  Active Hepatitis B or C infection

          -  Any other condition or circumstance (eg, clinical, psychological, familial,
             sociological, inability to swallow oral study drug) that, in the opinion of the
             investigator, may interfere with protocol compliance or contraindicates participation
             in the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 Dose (RP2D)
Time Frame:12 months
Safety Issue:
Description:RP2D as determined by 3+3 dose escalation design

Secondary Outcome Measures

Measure:Maximum plasma concentration (Cmax)
Time Frame:28 Days
Safety Issue:
Description:PK of ORIC-101 in combination with enzalutamide
Measure:Time of maximum observed concentration (Tmax)
Time Frame:28 Days
Safety Issue:
Description:PK of ORIC-101 in combination with enzalutamide
Measure:Area under the curve (AUC(0-24))
Time Frame:28 Days
Safety Issue:
Description:PK of ORIC-101 in combination with enzalutamide
Measure:Elimination half-life (T1/2)
Time Frame:28 Days
Safety Issue:
Description:PK of ORIC-101 in combination with enzalutamide
Measure:Circulating tumor cells (CTCs) conversion
Time Frame:36 months
Safety Issue:
Description:≥5 cells/7.5 mL of blood to 0 (zero) (CTC0), as well as from unfavorable (≥5 cells/7.5 mL of blood) to favorable (<5 cells/7.5 mL of blood)
Measure:Objective response rate (ORR)
Time Frame:36 months
Safety Issue:
Description:Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and PCWG3 criteria
Measure:Duration of response (DOR)
Time Frame:36 months
Safety Issue:
Description:Radiographic progression using RECIST v1.1
Measure:Progression-free survival (PFS)
Time Frame:36 months
Safety Issue:
Description:Time from first dose to first documentation of radiographic progression or death
Measure:Overall survival (OS)
Time Frame:36 months
Safety Issue:
Description:Time from first dose to death
Measure:Number of Participants with GR Expression by IHC
Time Frame:36 months
Safety Issue:
Description:Level of GR expression by IHC in tumor tissue samples

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Oric Pharmaceuticals

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