A Phase 1/2, Open-label, Dose Escalation, and Cohort Expansion Clinical Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of ARV-471 in Patients with ER+/HER2- Locally Advanced or Metastatic Breast Cancer, Who Have Received Prior Hormonal Therapy and Chemotherapy in the Locally Advanced/Metastatic Setting
This is a first in human, dose escalation study and will assess the safety and tolerability of ARV-471 in woman and men with ER+/HER2- locally advanced or metastatic breast cancer, who have received prior hormonal therapy and chemotherapy in the locally advanced/metastatic setting.
Primary: To evaluate the safety and tolerability of ARV-471in successive cohorts of patients in order to estimate the maximum tolerated dose and select the recommended phase 2 dose/schedule. Secondary: To characterize the single dose and steady-state PK of ARV-471 and ARV-473 (an epimer of ARV-471). To explore preliminary anti-tumor activity.
772256 (Palbociclib); ARV-471 (); Palbociclib ()
- At least 18 years of age or older at time of informed consent
- Must have histologically or cytologically confirmed ER+ and HER2- advanced breast cancer. Advanced breast cancer is metastatic, recurrent, or locally advanced unresectable breast cancer for which standard curative therapy is no longer effective or does not exist. ER+ disease must be documented by IHC per ASCO/CAP Guidelines. HER2- disease must be documented by either IHC or in-situ hybridization per ASCO/CAP guidelines.
- Must have measurable or nonmeasurable disease by RECIST 1.1, with radiologic tumor assessments performed within 28 days of the first dose of therapy.
- Women must be postmenopausal due to surgical or natural menopause, which requires at least 1 of the following: (a) prior bilateral oophorectomy, (b) 60 years of age or older, (c) Under 60 years and amenorrhoeic for at least 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and FSH and estradiol levels in the postmenopausal range; or ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a gonadotropin-releasing hormone agonist such as goserelin. Patients on ovarian suppression therapy should remain on such therapy in the absence of intolerable symptoms.
- > Men must agree to use contraception as detailed in Appendix 6 of this protocol during the treatment period and for 6 months after the last dose of study treatment and refrain from donating sperm during this period.
- Adequate bone marrow function and organ function as outlined per protocol.
- Any toxicity from prior anti-cancer therapy other than alopecia must have resolved to baseline severity or Grade 1 or less NCI-CTCAE Version 5.0
- Must agree and be capable or taking oral medication without crushing, dissolving, or chewing tablets.
- Phase 1 Dose Escalation: Patients must have received: at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or advanced/metastatic), a CDK4/6 inhibitor, up to 3 prior regimens of cytotoxic chemotherapy in the locally advanced or metastatic setting. All such therapy must be discontinued at least 14 days prior to enrollment.
- Phase 2 Expansion: At least 1 prior endocrine regimen for a maximum of 6 months in the locally advanced or metastatic setting; if more than 1 prior endocrine regimen has been administered, only 1 of the regimens must have been administered for a minimum of 6 months in the locally advanced or metastatic setting . No more than one prior chemotherapy regimen for advanced disease. All such therapy must be discontinued at least 14 days prior to enrollment.
- Phase 1: Patients must be willing to undergo a core biopsy of accessible tumor within 4 weeks prior to the initiation of study treatment and a follow up biopsy on-treatment for ER IHC testing and PD studies. (Patients without accessible tumor tissue may be eligible after discussion with the Medical Monitor).
- other criteria may apply
- 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.
- Phase 1: Patients who have received 4 or more regimens of chemotherapy for locally advanced or mBC.
- Phase 2: Patients who have received more than one regimen of chemotherapy for advanced/metastatic disease (regardless of prior adjuvant chemotherapy use) in addition to endocrine therapy.
- Receipt of prior anti-cancer or other investigational therapy within 14 days prior to the first administration of study drug. For prior therapies with a half-life longer than 3 days, the interval must equal 28 days prior to the first administration of study drug and the patient must have documented disease progression.
- Patients who have initiated therapy with bone-modifying agents (bisphosphonates, denosumab, or similar) within 14 days of enrollment. (Patients who are receiving bone-modifying agents are eligible for this study provided the bone-modifying agent was started more than 14 days prior to study enrollment.)
- 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. 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 (eg, opportunistic infections), and status of HIV treatment.
- Major surgery within 4 weeks of the first dose of study drug
- Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to greater than 25% of the bone marrow. Palliative radiation for the alleviation of pain due to bone metastasis will be allowed during the study.
- Previous high dose chemotherapy requiring stem cell rescue
- Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen in this study. Patients with a prior or concurrent malignancy whose natural history or treatment that does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen in this study may be eligible but must be discussed with the Medical Monitor.
- Other criteria may apply
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