A Phase 2 Study of ACR-368 in Endometrial Adenocarcinoma
- Conditions
- Endometrial Adenocarcinoma
- Interventions
- Registration Number
- NCT05548296
- Lead Sponsor
- Acrivon Therapeutics
- Brief Summary
This is an open label Phase 2 study to evaluate the efficacy and safety of ACR-368 as monotherapy or with ultra-low dose gemcitabine (ULDG) sensitization in participants with endometrial cancer.
- Detailed Description
OncoSignature Selected Cohorts (Arms 1 and 2):
Participants in Arms 1 \& 2 will be allocated into two arms based on prospectively predicted sensitivity to ACR-368 using the OncoSignature® Companion Diagnostic test, as follows:
Arm 1: OncoSignature Positive tumors
Arm 2: OncoSignature Negative tumors
OncoSignature Unselected Cohort (Arm 3):
In Arm 3 participants will not require a biopsy or OncoSignature result.
Participants in Arm 1 will receive ACR-368 as monotherapy. Participants in Arms 2 and 3 will receive ACR-368 with ULDG sensitization. Participants in all arms will be treated until disease progression, unacceptable toxicity or any criterion for stopping the study drug or withdrawal from the trial occurs.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Female
- Target Recruitment
- 353
General
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Participant must be able to give signed, written informed consent.
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Participant must have histologically documented, high-grade endometrial cancer.
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Treatment History Requirements:
- Subject must have received prior platinum-based chemotherapy
- Subject must have received prior anti-PD-(L)1 therapy
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Participant must have histologically confirmed metastatic cancer that has progressed during or after at least 1 prior therapeutic regimen.
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Participant must have at least 1 measurable lesion per RECIST v1.1 criteria (by local Investigator) in a baseline tumor imaging that has been obtained within 28 days of the treatment start. Participant must have radiographic evidence of disease progression based on RECIST v1.1 criteria following the most recent line of treatment.
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Arm 1 and 2 only: Participant must be willing to provide tissue from a newly obtained tumor biopsy from an accessible tumor lesion not previously irradiated after written informed consent.
Newly obtained is defined as a specimen taken after written informed consent is obtained, during the 28-day Screening period.
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Participant must be willing to provide an archival tumor tissue block or at least 20 unstained slides, if available.
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Participant must have stabilized or recovered (Grade 1 or baseline) from all prior therapy related toxicities, except as follows:
- Alopecia is accepted.
- Endocrine events from prior immunotherapy stabilized at ≤ Grade 2 due to need for replacement therapy are accepted (including hypothyroidism, diabetes mellitus, or adrenal insufficiency).
- Neuropathy events from prior cytotoxic therapies stabilized at ≤ Grade 2 are accepted.
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Participant must have an Eastern Cooperative Oncology Group Performance Status 0 or 1.
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Participant must have an estimated life expectancy of longer than 3 months.
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Participant must have adequate organ function at Screening, defined as:
- Absolute neutrophil count > 1500 cells/µL without growth factor support within 1 week prior to obtaining the hematology values at Screening.
- Hemoglobin ≥ 9.0 g/dL.
- Platelets ≥ 150,000 cells/µL without transfusion within 1 week prior to obtaining the hematology values at Screening.
- Calculated creatinine clearance (CrCl) ≥ 50 mL/min as calculated by the Cockcroft-Gault formula.
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); ≤ 5 × ULN if liver metastases are present.
- Total bilirubin ≤ 1.5 × ULN not associated with Gilbert's syndrome. If associated with Gilbert's syndrome ≤ 3 x ULN is acceptable.
- Serum albumin ≥ 3 g/dL.
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Participant must have adequate coagulation profile as defined below if not on anticoagulation. If subject is receiving anticoagulation therapy, then subject must be on a stable dose of anticoagulation for ≥ 1 month:
- Prothrombin time within 1.5 x ULN.
- Activated partial thromboplastin time within 1.5 x ULN.
General
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Participant with known symptomatic brain metastases requiring > 10 mg/day of prednisolone (or its equivalent). Participants with previously diagnosed brain metastases are eligible if they have completed their treatment, have recovered from the acute effects of radiation therapy or surgery prior to the start of ACR-368 treatment, fulfill the steroid requirement for these metastases, and are neurologically stable based on central nervous system imaging ≥ 4 weeks after treatment.
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Participant has mesenchymal tumors of the uterus.
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Participant has a history of clinically meaningful ascites, defined as history of paracentesis or thoracentesis with therapeutic intent, within 4 weeks of Screening. Subjects with planned therapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1 dosing are excluded.
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Participant had systemic therapy or radiation therapy within 3 weeks prior to the first dose of study drug.
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Participants has known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is considered uncontrolled based on the criteria included in Appendix 2.
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Participant has a history of clinically meaningful coagulopathy, bleeding diathesis.
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Participant has cardiovascular disease, defined as:
- Uncontrolled hypertension defined as blood pressure > 160/90 mmHg at Screening confirmed by repeat (medication permitted).
- History of torsades de pointes, significant Screening electrocardiogram (ECG) abnormalities, including ventricular rhythm disturbances, unstable cardiac arrhythmia requiring medication, pathologic symptomatic bradycardia, left bundle branch block, second degree atrioventricular (AV) block type II, third degree AV block, Grade ≥ 2 bradycardia, uncorrected hypokalemia not amenable to correction, congenital long QT syndrome, prolonged QT interval due to medications, corrected QT based on Fridericia's formula (QTcF) > 450 msec (for men) or > 470 msec (for women).
- Symptomatic heart failure (per New York Heart Association guidelines; (Caraballo, 2019), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction < 20%, transient ischemic attack, or cerebrovascular accident within 6 months of Day 1).
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Participant has a history of major surgery within 4 weeks of Screening.
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Participant has experienced bowel obstruction related to the current cancer within the last 6 months or signs or symptoms of intestinal obstruction, which include nausea, vomiting, or objective radiologic finding of bowel obstruction in the last 4 weeks before the start of the treatment.
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Participant has taken a prior cell cycle CHK1 inhibitor, including ACR-368
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description OncoSignature Positive Tumors ACR-368 ARM 1: Participants with OncoSignature Positive Tumors will enter a Phase 2 Simon 2-Stage Study that will assess the efficacy of ACR-368 as monotherapy. OncoSignature Positive Tumors OncoSignature ARM 1: Participants with OncoSignature Positive Tumors will enter a Phase 2 Simon 2-Stage Study that will assess the efficacy of ACR-368 as monotherapy. OncoSignature Negative Tumors ACR-368 Arm 2: Participants with OncoSignature Negative Tumors will receive ACR-368 with ULDG sensitization. The Phase 2 Study will assess the efficacy and safety of ACR-368 with ULDG sensitization. OncoSignature Negative Tumors Gemcitabine Arm 2: Participants with OncoSignature Negative Tumors will receive ACR-368 with ULDG sensitization. The Phase 2 Study will assess the efficacy and safety of ACR-368 with ULDG sensitization. OncoSignature Negative Tumors OncoSignature Arm 2: Participants with OncoSignature Negative Tumors will receive ACR-368 with ULDG sensitization. The Phase 2 Study will assess the efficacy and safety of ACR-368 with ULDG sensitization. OncoSignature Unselected (All-Comers) ACR-368 Arm 3: Participants who are OncoSignature Unselected (i.e. they will not require a newly obtained tumor biopsy or OncoSignature testing) will receive ACR-368 with ULDG sensitization. The Phase 2 Study will assess the efficacy and safety of ACR-368 with ULDG sensitization. OncoSignature Unselected (All-Comers) Gemcitabine Arm 3: Participants who are OncoSignature Unselected (i.e. they will not require a newly obtained tumor biopsy or OncoSignature testing) will receive ACR-368 with ULDG sensitization. The Phase 2 Study will assess the efficacy and safety of ACR-368 with ULDG sensitization.
- Primary Outcome Measures
Name Time Method Arm 1: Anti-tumor activity of ACR-368 in Endometrial cancer subjects that are OncoSignature Positive. Response will be assessed every 8 weeks from baseline through 2 years or death. Assess Objective Response Rate (ORR) per RECIST v1.1 by computed tomography or magnetic resonance imaging.
Arm 2: Anti-tumor activity of ACR-368 with ULDG sensitization in Endometrial cancer subjects that are OncoSignature Negative. Response will be assessed every 8 weeks from baseline through 2 years or death. Objective Response Rate (ORR) per RECIST v1.1 by computed tomography or magnetic resonance imaging.
Arm 3: Anti-tumor activity of ACR-368 with ULDG sensitization in Endometrial cancer subjects (All-Comers). Response will be assessed every 8 weeks from baseline through 2 years or death. Objective Response Rate (ORR) per RECIST v1.1 by computed tomography or magnetic resonance imaging.
- Secondary Outcome Measures
Name Time Method Arm 1: Adverse Events (AEs) for ACR-368 AEs will be assessed from baseline through 2 years or death. Safety will be assessed by the incidence of AEs characterized overall and by type, incidence, severity graded according to NCI CTCAE v5.0, seriousness, and relationship to study treatment.
Arm 2 and Arm 3: Adverse Events (AEs) for ACR-368 with ULDG sensitization AEs will be assessed from baseline through 2 years or death. Safety will be assessed by the incidence of AEs characterized overall and by type, incidence, severity graded according to NCI CTCAE v5.0, seriousness, and relationship to study treatment.
All Arms: Limited pharmacokinetic (PK) testing. Dose of ACR-368 at day 1 and day 15 of first cycle. Cmax and Tmax will be assessed in the first cycle. Blood samples will be collected at baseline, end of infusion, hour 2 and hour 4.
Overall Survival (OS) Up to 2 years The time from date of enrollment until date of death.
Duration of Response (DOR) Up to 2 years The time from initial response until investigator assessed progressive disease for all subjects who achieve a confirmed objective response.
Progression-free Survival (PFS) Up to 2 years The time from date of enrollment until disease progression or death whichever occurs first.
Trial Locations
- Locations (69)
University of South Alabama Mitchell Cancer Institute
🇺🇸Mobile, Alabama, United States
Alaska Women's Cancer Center
🇺🇸Anchorage, Alaska, United States
HonorHealth
🇺🇸Phoenix, Arizona, United States
Arizona Oncology Associate, PC- HOPE
🇺🇸Tucson, Arizona, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
City of Hope National Medical Center
🇺🇸Duarte, California, United States
UC San Diego Moores Cancer Center
🇺🇸La Jolla, California, United States
USC/Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Cedars Sinai Medical Center
🇺🇸Los Angeles, California, United States
Hoag Cancer Center
🇺🇸Newport Beach, California, United States
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