Relacorilant and Nab-Paclitaxel in Recurrent or Metastatic Cervical Cancer

Recurrent or metastatic cervical cancer remains associated with poor outcomes after progression following platinum-based chemotherapy and immune checkpoint inhibitor therapy. Available subsequent treatment options are limited and are generally associated with modest clinical benefit.

Glucocorticoid receptor signaling may contribute to tumor cell survival, immune evasion, and resistance to anticancer therapy. Relacorilant is a selective glucocorticoid receptor modulator that may enhance sensitivity to taxane-based chemotherapy. The combination of relacorilant and nab-paclitaxel has demonstrated antitumor activity in previous clinical studies in other tumor types.

STELLA is a prospective, multicenter, open-label, single-arm phase II study designed to evaluate relacorilant in combination with nab-paclitaxel in participants with recurrent or metastatic cervical cancer previously exposed to platinum-based chemotherapy and immune checkpoint inhibition, if eligible. Approximately 63 participants are planned to be enrolled at approximately 22 sites.

Nab-paclitaxel will be administered intravenously at 80 mg/m² on Days 1, 8, and 15 of each 28-day cycle. Relacorilant will be administered orally at 150 mg once daily on the day before, the day of, and the day after each nab-paclitaxel administration, except that relacorilant will not be administered on the day before the first nab-paclitaxel dose at Cycle 1 Day 1.

The primary endpoint is objective response rate according to RECIST version 1.1, defined as the proportion of participants achieving a complete response or partial response as their best overall response during the study. The study will also assess duration of response, progression-free survival, overall survival, safety, and exploratory translational objectives.

Inclusion criteria

• Histologically confirmed diagnosis of squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix.
• Recurrent or metastatic cervical cancer:
• Has progressed on or after treatment with 1 prior line of systemic platinum doublet chemotherapy, with or without bevacizumab. Prior chemoradiotherapy in the Locally Advanced Cervical Cancer (LACC) setting is not considered a line of treatment.
• Has received anti-PD-1/anti-PD-L1 therapy as part of a prior cervical cancer treatment regimen, if eligible.
• Has received no more than 3 prior systemic regimens for advanced disease, with no more than one line of single-agent chemotherapy, and/or no more than one antibody-drug conjugate (ADC) therapy.
• Has received no prior treatment with weekly paclitaxel, other than a front-line combination treatment as part of a platinum doublet regimen.
• Has measurable disease per RECIST v1.1, as assessed by the investigator. Lesions situated in a previously irradiated area are considered measurable if radiographic progression has been demonstrated in such lesions.
• Has provided documented informed consent.
• Is assigned female sex at birth and is at least 18 years of age at the time of providing informed consent.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days before inclusion.
• Has consented to provide available formalin-fixed paraffin-embedded (FFPE) tumor tissue from a core/excisional biopsy or surgical resection specimen. If unavailable, the most representative FFPE tumor block of the disease should be provided.
• Adverse events due to previous anticancer therapies must have recovered to Grade ≤1 or baseline, except alopecia or vitiligo. Participants with endocrine-related adverse events who are adequately treated with hormone replacement therapy are eligible.
• Participants with HIV infection must have well-controlled HIV on antiretroviral therapy (ART), defined as:
• CD4+ T-cell count ≥350 cells/mm³ at screening.
• Confirmed HIV RNA below 50 copies/mL or below the lower limit of quantification for at least 12 weeks before screening.
• No AIDS-defining opportunistic infection within the previous 12 months.
• Stable ART regimen without changes in drugs or dose modification for at least 4 weeks before inclusion, with agreement to continue ART throughout the study. The ART regimen must not contain strong CYP3A4 inducers or CYP3A substrates that cannot be dose-adjusted when coadministered with strong CYP3A inhibitors.
• Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to inclusion.
• Has adequate organ function:
• Absolute neutrophil count ≥1,500 cells/mm³ without G-CSF support within 2 weeks before screening laboratory sample collection.
• Platelet count ≥100,000/mm³ without transfusion within 2 weeks before screening laboratory sample collection.
• Hemoglobin ≥9 g/dL without transfusion within 2 weeks before screening laboratory sample collection.
• AST and ALT ≤2.5 × upper limit of normal (ULN), or ≤5 × ULN in the presence of liver metastases.
• Total bilirubin ≤1.5 × ULN, or ≤3 × ULN for participants with Gilbert's syndrome.
• Albumin ≥2.5 g/dL.
• Calculated creatinine clearance ≥30 mL/min, with full recovery from any episode of acute renal failure.
• Participants of childbearing potential must have a negative pregnancy test and agree to use highly effective contraception; hormonal contraceptives are not allowed.
• Is affiliated with a social insurance regimen.
• Is willing and able to comply with the protocol for the duration of the study, including treatment, scheduled visits, examinations, and follow-up.

Exclusion criteria

• Grade ≥2 peripheral neuropathy.
• Active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease, including Crohn's disease, ulcerative colitis, or chronic diarrhea.
• Clinically relevant and reversible toxicity from prior systemic anticancer therapies or radiotherapy that has not resolved to Grade ≤1 before enrollment, except alopecia, hearing loss, vitiligo, and endocrinopathy managed with replacement therapy.
• Surgery within 4 weeks prior to enrollment or anticipated requirement for a surgical procedure during the study. Participants must have adequately recovered from toxicity and/or complications of prior major surgery.
• Has received any of the following before enrollment:
• Chemotherapy, immunotherapy, investigational agent, or other treatment for the disease under study within 5 half-lives of the prior therapy, or 28 days if 5 half-lives is longer than 28 days, before the first dose of study treatment.
• Radiotherapy not completed at least 2 weeks before the first dose of study treatment.
• Systemic, inhaled, or prescription-strength topical corticosteroids within a period equivalent to 5 half-lives of the corticosteroid before the first dose.
• Wide-field radiation therapy to more than 25% of marrow-bearing areas.
• Requires chronic or frequently used systemic corticosteroids for medical conditions or illnesses.
• History of severe hypersensitivity or severe reaction to any study treatment.
• Has received prior treatment with mifepristone or another glucocorticoid receptor modulator as part of a treatment regimen for cervical cancer.
• Is pregnant, breastfeeding, or planning to conceive during the projected duration of the study through at least 6 months after the last dose of study treatment.
• Has clinically significant uncontrolled condition(s) that, in the investigator's opinion, may confound study results or interfere with participant safety or participation, including but not limited to:
• Unstable angina.
• Myocardial infarction within 6 months before the first dose.
• New York Heart Association Class II or greater congestive heart failure.
• Serious cardiac arrhythmia requiring medication or prolongation of QTcF.
• Severe or advancing cirrhosis.
• Active infectious disease requiring intravenous therapy within 2 weeks before the first dose.
• Gastric-outlet obstruction.
• Acute renal failure that has not recovered to baseline renal function.
• Known psychiatric disorder that would interfere with study compliance.
• Current uncontrolled chronic or acute infection with HIV, hepatitis C virus, or hepatitis B virus.
• Untreated, symptomatic, or corticosteroid-dependent central nervous system metastases.
• History of another malignancy within 3 years before enrollment, except tumors with negligible risk of metastasis or death, such as adequately controlled basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast.
• Is taking a prohibited concomitant medication specified in the protocol.
• Is receiving concurrent treatment in another investigational treatment study for cervical cancer.
• Has received a live vaccine within 30 days before study treatment. Injectable seasonal influenza vaccines are generally inactivated and are permitted; intranasal live attenuated influenza vaccines are prohibited.
• Is deprived of liberty, under guardianship or curatorship, or otherwise meets the legal definition of a vulnerable person under Regulation (EU) No. 536/2014.