MC# 21-09 - A Phase I/II, Open-Label, Dose Escalation, and Cohort Expansion Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ARV-110 in Patients with Metastatic Castration Resistant Prostate Cancer

  • Agent(s): ARV-110
  • Disease Type(s): Prostate
  • Phase(s): I, II
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): AR
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Mechanism of Action

ARV-110 targets and binds to the AR ligand binding domain.  E3 ligase is recruited to the AR by the E3 ligase recognition moiety and the AR target protein is tagged by ubiquitin.  This causes ubiquitination and degradation of AR by the proteasome.  This prevents the expression of AR target genes and halts AR-mediated signaling.  This results in an inhibition of proliferation in AR-overexpressing tumor cells.  In addition, the degradation of the AR protein releases the ARV-110 and it can bind to additional AR target proteins.

Purpose

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

  • About the safety and tolerability of ARV-110
  • The positive and negative effects of ARV-110
  • How much of ARV-110 is absorbed into the blood and how fast it is removed
  • If ARV-110 prevents or delays tumor growth
Inclusion Criteria
  1. Patients must be male and at least 18 years of age inclusive, at the time of signing the informed consent
  2. Patients with histological, pathological, or cytological confirmed diagnosis of advanced or metastatic castration resistant adenocarcinoma of the prostate
  3. Patients must have received at least 1 but no more than 2 prior second generation antiandrogen agents (e.g., enzalutamide or abiraterone) for CRPC
  4. Patients must have received no more than 1 prior chemotherapy regimen in each of the following settings: castrate sensitive and castrate resistant prostate cancer
  5. Patients with progressive mCRPC defined as:
    1. Serum testosterone levels less than 50 ng/dL (or ≤0.50 ng/mL or 1.73 nmol/L) using ultrasensitive testosterone assays with a sensitivity of 1 to 2 ng/dL, within 28 days before study drug treatment.
    2. Radiographic evidence of metastatic disease.
    3. Disease progression on or since most recent systemic therapy as evidenced by a sequence of at least 2 rising PSA values measured at a minimum of 1 week apart with a 2 ng/mL minimum starting value. Evidence of PSA progression may or may not be accompanied by progression in soft tissue or bone.
  6. Tumors harboring AR T878 and/or H875 mutations
  7. Patients must have ongoing ADT with a gonadotropin releasing hormone analog or inhibitor, or orchiectomy (surgical or medical castration)
  8. Patients must agree to take oral medication with food, without crushing, dissolving, or chewing tablets
  9. Patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1
  10. Patients must have adequate bone marrow function defined as follows (with no transfusion of blood products or use of hematopoietic growth factors in the 28 days prior to enrollment):
    1. Absolute neutrophil count of ≥1500/mm3 or ≥1.5 × 109/L.
    2. Platelets of ≥100,000/mm3 or ≥100 × 109/L.
    3. Hemoglobin ≥9 g/dL.
  11. Patients must have adequate renal function defined as serum creatinine of ≤1.5 × ULN or an estimated creatinine clearance of ≥50 mL/min by Cockcroft Gault.
  12. Patients must have adequate liver function defined as:
    1. Total serum bilirubin of ≤1.5 × ULN unless the patient has documented Gilbert syndrome
    2. AST and ALT of ≤2.5 × ULN if there is NO liver involvement secondary to tumor OR ≤5.0 × ULN if there is liver involvement secondary to tumor
  13. Patients must have resolved acute effects of any prior therapy to baseline severity or Grade ≤1 by NCI CTCAE except for the following:
    1. alopecia
    2. peripheral neuropathy.
  14. Patients receiving steroids should be on a stable steroid dose of no more than 10 mg per day of prednisone/prednisolone or its equivalent for at least 2 weeks prior to enrollment.
  15. Patients able to father children affirm they meet the criteria for correct use of 2 of the selected methods of contraception, as described in Appendix 6 of this protocol during the treatment period and for at least 35 days after the last dose of study treatment and refrain from donating sperm for 6 months after the last dose of study drug.
  16. Patients must be willing and capable of giving signed informed consent as described in Appendix 2, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol.
  17. Results of tumor DNA sequence analysis, including the AR gene, must be known prior to initiation of treatment based on either prior historical DNA testing performed at a CLIA certified laboratory within 3 months of enrollment or central ctDNA testing performed during screening. Patients whose results are delayed due to technical issues may be granted inclusion by the Arvinas Medical Monitor.

 

Exclusion Criteria
  1. Patients with known symptomatic brain metastases requiring steroids (above physiologic replacement doses). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to first dose of study drug have discontinued high-dose corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable as judged by the Investigator.
  2. Major surgery (as judged by the Investigator) within 4 weeks of first dose of study drug.
  3. Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to >25% of the bone marrow. Palliative radiation for the alleviation of pain due to bone metastasis will be allowed during the study.
  4. Systemic anti-cancer therapy (e.g., enzalutamide) within 2 weeks of first dose of study drug (6 weeks for bicalutamide, mitomycin C, or nitrosoureas and 4 weeks for abiraterone). Patients are ineligible if they received any other type of anti-cancer agent (except agents to maintain castrate status) within 2 weeks before first dose of study drug.
  5. Previous high-dose chemotherapy requiring stem cell rescue.
  6. Patients with any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ, or other low grade localized cancer. Eligibility for exception requires Medical Monitor approval.
  7. Prior treatment with ARV-110 or another protein degrader compound that targets the ligand binding domain of the AR.
  8. Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association class III or IV), cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, or other clinically significant episode of thromboembolic disease.
  9. Any of the following in the previous 6 months: Congenital long QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), left anterior hemiblock (bifascicular block). Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, atrial fibrillation of any grade (Grade ≥2 in the case of asymptomatic lone atrial fibrillation). Anticoagulation (heparin only, no vitamin K antagonists or factor Xa inhibitors) can be allowed if indicated. If a patient has a cardiac rhythm device/pacemaker placed and QTcF >470 msec, the patient can be considered eligible. Patients with cardiac rhythm device/pacemaker must be discussed in detail with the Medical Monitor to judge eligibility.
  10. Hypertension that cannot be controlled by medications (>150/90 mmHg despite optimal medical therapy).
  11. Patients with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C virus, known HIV, or AIDS-related illness. In equivocal cases, patients whose viral load is negative, may be eligible. The HIV seropositive patients who are healthy and low risk for AIDS-related outcomes could be considered eligible. Eligibility criteria for HIV positive patients should be evaluated and discussed with the Medical Monitor and will be based on current and past CD4 and T-cell counts, history (if any) of AIDS-defining conditions (e.g., opportunistic infections), and status of HIV treatment.
  12. Receipt of an investigational drug(s) within 1 month prior to anticipated first dose of study drug. A patient may be eligible if a long-term follow-up from prior investigational studies has been met. Cases must be discussed with the Medical Monitor to judge eligibility.
  13. Suspected hypersensitivity to ARV-110.
  14. Other acute or chronic severe medical or psychiatric condition, including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
  15. Active inflammatory GI disease, chronic diarrhea, known diverticular disease, or previous gastric resection or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed.
  16. Patients who fall into any of the following:
    1. Investigational site staff members directly involved in the conduct of the study and their family members, OR
    2. Site staff members otherwise supervised by the Investigator, OR
    3. Patients employed by the Sponsor who are directly involved in the conduct of the study.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03888612

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Re: MC# 21-09