MC# 20-39 - An Open-label Phase Ib Study of ORIC-101 in Combination with Anticancer Therapy in Patients with Advanced or Metastatic Solid Tumors

  • Agent(s): ORIC-101
  • Disease Type(s): Ovarian, Pancreatic, Solid Tumor, Breast- Triple Negative
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): GR (Glucocorticoid receptor)

Mechanism of Action

ORIC-101 selectively binds to Glutocorticoid Receptors, thereby inhibiting the activation of GR-mediated proliferative and anti-apoptotic gene expression pathways.  Inhibition of GR activity may potentially slow tumor cell growth and disease progression in certain cancers.

Purpose

 In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of ORIC-101 in combination with nab-paclitaxel
  • How proteins that indicate the status of your disease are affected with use of ORIC-101
  • If ORIC-101 in combination with nab-paclitaxel prevents or delays tumor growth or shrinks existing tumors
  • How much of ORIC-101 is absorbed into the blood and how fast it is removed
Inclusion Criteria
  1. Histological type and prior therapy/lines of therapy
    • PDAC
      • Advanced or metastatic pancreatic ductal adenocarcinoma previously treated with and progressed on a fluoropyrimidine-based regimen and a taxane- containing chemotherapy regimen (eg, gemcitabine + nab-paclitaxel)
      • Pancreatic neuroendocrine tumors, lymphoma of the pancreas, acinar pancreatic cancer, or ampullary cancer are not eligible
    • Ovarian Cancer
      • Advanced or metastatic high grade serous or endometrioid epithelial ovarian, primary peritoneal, fallopian tube cancer or ovarian carcinosarcoma, previously treated with and progressed on a taxane- containing chemotherapy regimen
      • Clear cell, mucinous and borderline histologic subtypes are not eligible
      • Received at least one line of therapy with evidence of cancer progression within 6 months after the last dose of platinum-based therapy (ie, having a platinum-free interval of<6 months [platinum resistant]), or progressive disease during or immediately after primary platinum-therapy, (ie, platinum refractory).  Note: For the calculation of the platinum-free interval, cancer progression must be defined by clear evidence of progression, such as radiographic progression per RECIST 1.1.  Calculating the platinum-free interval on the basis of increased CA-125 is not allowed.
    • TNBC
      • Advanced or metastatic ER- negative, PR-negative, HER2- negative primary breast cancer previously treated and progressed on a taxane-based chemotherapy regime.  Note: ER <10%, PR <10% allowed.
      • No previous or synchronous second breast cancer, unless also confirmed ER-, PR- and HER2-negative
      • Received at least one line of therapy in the metastatic setting
    • Other Solid Tumors
      • Other advanced or metastatic solid tumor previously treated with and progressed on a taxane-based chemotherapy regimen, with the exception of metastatic colorectal cancer, primary brain tumors, and neuroendocrine tumors that secrete ACTH or CRH
      • Received no more than 4 prior lines of cytotoxic or myelosuppressive therapy
  2. Age, gender, ECOG performance status
    • PDAC
      • At least 18 years of age
      • Male and female
      • ECOG 0-1
    • Ovarian Cancer
      • At least 18 years of age
      • Female
      • ECOG 0-1
    • TNBC
      • At least 18 years of age
      • Female
      • ECOG 0-1
    • Other Solid Tumors
      • At least 18 years of age
      • Male and female
      • ECOG 0-1
  3. Measurable disease as assessed centrally using RECIST 1.1; previously irradiated lesions are not allowed as measurable disease, unless there is documented evidence of progression in the lesions
  4. For patients with treated, stable CNS metastases that are asymptomatic: no evidence of progression for at least 4 weeks after CNS-directed treatment as determined by clinical examination and brain imaging. Patients must not require steroids and must be neurologically stable without corticosteroids for a minimum of 3 weeks prior  to Cycle 1 Day 1
  5. Agreement and ability to undergo two on-study biopsies, as follows, through a procedure that is deemed to be clinically feasible and not carry significant risk:
    • one pre-treatment tumor biopsy obtained prior to dosing; and
    • one post-treatment tumor biopsy during Cycle 2
  6. 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)
    • Albumin ≥3.0 g/dL
    • 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 ≤480 msec
  7. Ability to swallow ORIC-101 intact without chewing or crushing the capsules or tablets
  8. Adequate gastrointestinal absorption.  If the patient has undergone gastric bypass surgery and/or surgery of gastrointestinal or hepatobiliary tract, the patient must demonstrate adequate absorption as evidenced by albumin ≥3.0 g/dL, controlled pancreatic insufficiency (if present), and lack of evidence of malabsorption.
  9. Female patients must not be pregnant, breastfeeding, and at least one of the following conditions apply: is not a woman of child-bearing potential (WOCBP); OR is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year) with low user dependency during the treatment period and for at least 1 month after the last dose of study treatment; a WOCBP must have a negative highly sensitive serum pregnancy test within 72 hours before the first dose of study treatment
  10. Male patients
    • PDAC and Other Solid Tumors
      • Must agree to the following during the treatment period and for at least 1 month after  the  last dose of study treatment: refrain from donating sperm; AND either be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent; OR use a male condom and be advised of the benefit for a female partner to use a highly effective method of contraception
  11. Willingness to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
  12. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to the start of study treatment
Exclusion Criteria
  1. Any other current or active malignancy
  2. Prior or current treatment with ORIC-101 or any other GR antagonist (eg, mifepristone, relacorilant)
  3. Concurrent treatment with any other anticancer therapy including chemotherapy, hormonal therapy, immunotherapy, radiotherapy, chemoembolization, targeted therapy, or an investigational agent within 28 days prior to Cycle 1 Day 1
  4. Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or incomplete recovery from adverse effects resulting from such procedures; palliative radiotherapy within 1 week of Cycle 1 Day 1
  5. Systemic, inhaled, or prescription strength topical corticosteroids within 21 days prior to Cycle 1 Day 1; short courses (≤5 days) for non-cancer-related reasons are allowed if clinically required
  6. Grade 2 (moderate) or higher peripheral neuropathy per CTCAE v5.0; patients with mild peripheral neuropathy may be eligible at the discretion of the investigator in consultation with ORIC
  7. All other toxicities from prior therapy (except alopecia) that have not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 ≤ Grade 1
  8. Females: history of unexplained vaginal bleeding in the 8 weeks prior to Cycle 1 Day 1 (given potential for ORIC-101 to exacerbate such bleeding)
  9. Females: use of hormone replacement therapy; hormone replacement therapy must be discontinued to allow for confirmation of postmenopausal status
  10. History of Cushing’s syndrome or adrenal insufficiency
  11. Current (within 10 days prior to Cycle 1 Day 1) or expected on-study treatment with specified strong CYP3A4 inhibitors or inducers
  12. Known human immunodeficiency virus (HIV) infection, unless patient is healthy and has a low risk of AIDS-related outcomes
  13. Presence of Hepatitis B surface antigen (HBsAg) at screening
  14. Positive Hepatitis C (HCVAb) antibody test result at screening or within 3 months prior to Cycle 1 Day 1.  NOTE: Patients with positive HCVAb due to prior resolved disease can be enrolled if a confirmatory negative Hepatitis C RNA test is obtained.
  15. Positive Hepatitis C RNA test result at screening or within 3 months prior to Cycle 1 Day 1.  NOTE: Test is optional and patients with negative HCVAb test are not required to also undergo Hepatitis C RNA testing.
  16. Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator, contraindicates participation in the study
  17. Any other condition or circumstance (eg, familial, sociological) that, in the opinion of the investigator, may interfere with protocol compliance or contraindicates participation in the study

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://www.clinicaltrials.gov/ct2/show/NCT03928314

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Re: MC# 20-39