A Study of ACR-368 in Ovarian Carcinoma, Endometrial Adenocarcinoma, and Urothelial Carcinoma

Phase 1

Recruiting

• Conditions: Endometrial Adenocarcinoma; Urothelial Carcinoma; Platinum-resistant Ovarian Cancer
• Interventions: Drug: ACR-368; Diagnostic Test: OncoSignature; Drug: Gemcitabine

• Registration Number: NCT05548296
• Lead Sponsor: Acrivon Therapeutics

Brief Summary

This is an open label Phase 1b/2 study to evaluate the efficacy and safety of ACR-368 as monotherapy or in combination with ultralow dose gemcitabine in participants with platinum-resistant ovarian carcinoma, endometrial adenocarcinoma, and urothelial carcinoma based on Acrivon's OncoSignature® test status.

Detailed Description

Participants will be selected for predicted efficacy of ACR-368 using the OncoSignature® Companion Diagnostic test. Participants will be allocated to one of 2 arms based on OncoSignature result:

Arm 1: OncoSignature Positive tumors

Arm 2: OncoSignature Negative

Participants in Arm 1 will receive ACR-368 as monotherapy. Participants in Arm 2 will receive the combination of ACR-368 and ultralow-dose gemcitabine. Participants in both arms will be treated until disease progression, unacceptable toxicity or any criterion for stopping the study drug or withdrawal from the trial occurs.

Study Timeline

• Study Start: 2022-08-29
• Study First Submitted: 2022-08-29
• Study First Submitted QC: 2022-09-16
• Study First Posted: 2022-09-21
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-11
• Last Update Posted: 2025-04-15
• Primary Completion: 2026-07-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 390

Inclusion Criteria

General

1. Participant must be able to give signed, written informed consent.

2. Participant must have histologically confirmed, locally advanced (i.e., not amenable to curative surgery and/or radiation therapy) or metastatic cancer that has progressed during or after at least 1 prior therapeutic regimen.

3. Participant must have at least 1 measurable lesion per RECIST v1.1 criteria (by local Investigator) (Eisenhauer, 2009) 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. Biochemical recurrence (eg, cancer antigen [CA-125] in ovarian carcinoma) only is not considered as disease progression.

4. 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.

5. Participant must be willing to provide an archival tumor tissue block or at least 20 unstained slides, if available.

6. Participant must have stabilized or recovered (Grade 1 or baseline) from all prior therapy related toxicities, except as follows:

   1. Alopecia is accepted.
   2. Endocrine events from prior immunotherapy stabilized at ≤ Grade 2 due to need for replacement therapy are accepted (including hypothyroidism, diabetes mellitus, or adrenal insufficiency).
   3. Neuropathy events from prior cytotoxic therapies stabilized at ≤ Grade 2 are accepted.

7. Participant must have an Eastern Cooperative Oncology Group Performance Status 0 or 1.

8. Participant must have an estimated life expectancy of longer than 3 months.

9. Participant must have adequate organ function at Screening, defined as:

   1. Absolute neutrophil count > 1500 cells/µL without growth factor support within 1 week prior to obtaining the hematology values at Screening.
   2. Hemoglobin ≥ 9.0 g/dL without transfusion or growth factor support within 2 weeks prior to obtaining the hematology values at Screening.
   3. Platelets ≥ 100,000 cells/µL without transfusion within 1 week prior to obtaining the hematology values at Screening.
   4. Calculated creatinine clearance ≥ 30 mL/min as calculated by the Cockcroft Gault formula.
   5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); ≤ 5 × ULN if liver metastases are present.
   6. Total bilirubin ≤ 1.5 × ULN not associated with Gilbert's syndrome. If associated with Gilbert's syndrome ≤ 3 x ULN is acceptable.
   7. Serum albumin ≥ 3 g/dL.

10. 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:

    1. Prothrombin time within 1.5 x ULN.
    2. Activated partial thromboplastin time within 1.5 x ULN.

Tumor Specific Inclusion Criteria

For Ovarian Carcinoma:

1. Participant must have histologically documented, advanced metastatic and/or unresectable) platinum resistant high-grade serous/endometrioid ovarian, primary peritoneal, or fallopian tube cancer. Platinum-resistant disease is defined as progression or relapse within 6 months after the completion of platinum-based therapy.

   a. Carcinosarcoma is eligible.

2. Participant must have received at least 1 but no more than 6 prior lines of systemic therapy, including at least 1 line of therapy containing platinum derivative and taxane, and single-agent therapy must be appropriate as the next line of treatment:

3. Participant must have had prior bevacizumab or did not receive bevacizumab based on Investigator judgment (see Section 2.1.1).

4. Participants with or without documented test results assessing alterations in the DNA repair pathway genes, eg, Breast Cancer gene 1 (BRCA1), BRCA2, and homologous recombination deficiency, at Screening are eligible. Subjects with known BRCA mutated tumors should have received a PARP inhibitor maintenance or treatment.

5. Participant will be enrolled regardless of tumoral folate receptor alpha (FRα) expression status. FRα expression status will be collected for retrospective analysis, if the information is available.

For Endometrial Carcinoma

1. Participant must have histologically documented, high-grade endometrial adenocarcinoma.

   1. All Grade 3 International Federation of Gynecology and Obstetrics epithelial endometrial histological subtypes are eligible including: endometrioid, serous, and clear-cell carcinoma.
   2. Carcinosarcoma is eligible.
   3. Participant must have no more than 4 prior lines of therapy in the recurrent setting, including platinum-based chemotherapy for subtypes of endometrial adenocarcinoma where it is a standard of care. The four lines of therapies must not include more than 3 lines containing a cytotoxic regimen.

2. Participant must have documented failure (includes treatment discontinuation related to toxicity) or ineligibility (based on Investigator judgement) for prior anti-programmed cell death protein 1/anti-programmed death- ligand 1 (anti-PD 1/anti-PD L1) based therapy for advanced/metastatic disease. Prior combination of PD 1/PD L1 inhibitor and vascular endothelial growth factor tyrosine kinase inhibitor (TKI) is acceptable.

3. Prior neoadjuvant or adjuvant chemotherapy included in initial treatment are not considered first- or later-line treatment unless such treatments were completed less than 6 months prior to the current tumor recurrence. Prior treatment may include chemotherapy, chemotherapy/radiation therapy, and/or consolidation/maintenance therapy.

4. Prior treatment with hormonal therapy or inhibitors of the mTOR or CDK4/6 pathways are not considered a line of therapy in any setting.

For Urothelial Carcinoma

1. Participant must have histologically documented, advanced (metastatic and/or unresectable) urothelial carcinoma. Variant histology is allowed as long as the tumor is predominantly urothelial.

2. Participants must have:

   1. Received a platinum containing regimen (cisplatin or carboplatin) in the metastatic/locally advanced, neoadjuvant, or adjuvant setting. If platinum was administered in the adjuvant/neoadjuvant setting, participant must have progressed within 12 months of completion.
   2. Been exposed to or have been ineligible for checkpoint inhibitors (including PD-1 or PD-L1 inhibitors).
   3. Been exposed to or have been ineligible for enfortumab vedotin.

Exclusion Criteria

General

1. 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.

2. Participant had systemic therapy or radiation therapy within 2 weeks prior to the first dose of study drug.

3. Participants has known human immunodeficiency virus, hepatitis B, or hepatitis C infection that is considered uncontrolled based on the criteria included in Appendix 2.

4. Participant has a history of clinically meaningful coagulopathy, bleeding diathesis.

5. Participant has cardiovascular disease, defined as:

   1. Uncontrolled hypertension defined as blood pressure > 160/90 mmHg at Screening confirmed by repeat (medication permitted).
   2. 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).
   3. 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).

6. Participant has a history of major surgery within 4 weeks of Screening.

7. Participant has a history of bowel obstruction related to the current cancer or participant has 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.

8. Participant has taken a prior cell cycle CHK1 inhibitor, including ACR-368

Tumor Specific Exclusion Criteria

For Ovarian Carcinoma:

1. Participant has non-epithelial carcinoma, clear-cell, mucinous, germ-cell, low-grade serous, or low-grade endometrioid carcinoma.
2. Participant has a history of clinically meaningful ascites, defined as a history of paracentesis or thoracentesis within 4 weeks of Screening. Participant has a planned therapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1 dosing.
3. Participant has a history of active inflammatory bowel disease within 2 years prior to Screening.
4. Participant has a history of bowel perforation, fistula, necrosis, or leak within 8 weeks of Screening.

For Endometrial Adenocarcinoma:

1. Participant has low-grade endometrioid carcinoma.
2. Participant has mesenchymal tumors of the uterus.
3. Participant has a history of clinically meaningful ascites, defined as a history of paracentesis or thoracentesis within 4 weeks of Screening. Participant has a planned therapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1 dosing.

For Urothelial Carcinoma:

1. Participant has sarcoma, carcinosarcoma, melanoma, or lymphoma of the bladder.
2. Participant has not received a previous platinum-based regimen.
3. Participant has small cell or neuroendocrine histology.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
OncoSignature Positive Tumors	ACR-368	In Arm 1, participants with an OncoSignature Positive test will enter a Phase 2 Simon 2-Stage Study that will assess the efficacy of ACR-368 as monotherapy in each of the 3 cohorts of participants (ovarian, endometrial, and urothelial).
OncoSignature Positive Tumors	OncoSignature	In Arm 1, participants with an OncoSignature Positive test will enter a Phase 2 Simon 2-Stage Study that will assess the efficacy of ACR-368 as monotherapy in each of the 3 cohorts of participants (ovarian, endometrial, and urothelial).
OncoSignature Negative	ACR-368	In Arm 2, participants with an OncoSignature Negative will receive the combination of ACR-368 and ultralow Dose Gemcitabine (ULDG). The Phase 1b/2 portion will only enroll participants with OncoSignature Negative tumors. Unevaluable tumors will not be able to participate. A Phase 1b Study will assess the safety of the combination of ACR-368 and escalating doses of ULDG in participants with any of the 3 tumor types (ovarian, endometrial, and urothelial). The Phase 1b Study will determine the recommended Phase 2 dose (RP2D) of ULDG. A Phase 2 Exploratory Study will assess the efficacy and safety of the combination of ACR-368 and the RP2D of ULDG in each of the 3 cohorts of participants (ovarian, endometrial, and urothelial).
OncoSignature Negative	Gemcitabine	In Arm 2, participants with an OncoSignature Negative will receive the combination of ACR-368 and ultralow Dose Gemcitabine (ULDG). The Phase 1b/2 portion will only enroll participants with OncoSignature Negative tumors. Unevaluable tumors will not be able to participate. A Phase 1b Study will assess the safety of the combination of ACR-368 and escalating doses of ULDG in participants with any of the 3 tumor types (ovarian, endometrial, and urothelial). The Phase 1b Study will determine the recommended Phase 2 dose (RP2D) of ULDG. A Phase 2 Exploratory Study will assess the efficacy and safety of the combination of ACR-368 and the RP2D of ULDG in each of the 3 cohorts of participants (ovarian, endometrial, and urothelial).
OncoSignature Negative	OncoSignature	In Arm 2, participants with an OncoSignature Negative will receive the combination of ACR-368 and ultralow Dose Gemcitabine (ULDG). The Phase 1b/2 portion will only enroll participants with OncoSignature Negative tumors. Unevaluable tumors will not be able to participate. A Phase 1b Study will assess the safety of the combination of ACR-368 and escalating doses of ULDG in participants with any of the 3 tumor types (ovarian, endometrial, and urothelial). The Phase 1b Study will determine the recommended Phase 2 dose (RP2D) of ULDG. A Phase 2 Exploratory Study will assess the efficacy and safety of the combination of ACR-368 and the RP2D of ULDG in each of the 3 cohorts of participants (ovarian, endometrial, and urothelial).

Primary Outcome Measures

Name	Time	Method
Arm 1 Monotherapy: Anti-tumor activity of ACR-368 in Ovarian, Endometrial, and Urothelial Cohorts	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 for the number of participants with a partial or complete response.
Arm 2 Phase 1b: Adverse Events (AEs) for ACR-368 in combination with ULDG	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 Phase 1b: Determine the RP2D of ULDG	AEs will be assessed from first dose of ULDG for 28 days for each subject in a cohort.	The RP2D will be evaluated by the incidence of DLT events per dose level.
Arm 2 Exploratory Phase 2: Anti-tumor activity of ACR-368 plus ULDG in Ovarian, Endometrial and Urothelial Cohorts	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 for the number of participants with a partial or complete response.

Secondary Outcome Measures

Name	Time	Method
Arm 1: Number of subjects with confirmed OncoSignature thresholds for enrichment of ACR-368 monotherapy responders	Baseline to first post treatment imaging at 8 weeks	Response data including tumor shrinkage at first imaging and progression by computed tomography or magnetic resonance imaging for the first 12 participants in each tumor type
Arm 1: Adverse Events (AEs) for ACR-368 monotherapy	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.
Relative dose intensity of ACR-368	First dose of ACR-368 in first cycle to dose on day 15 of second cycle of administration.	Assess the ratio of cumulative administered dose to the planned dose for first 2 cycles
Arm 1: Limited pharmacokinetic (PK) testing in participants with Ovarian Carcinoma	Dose of ACR-368 at day 1 and day 15 of first cycle	Cmax will be assessed in the first cycle at baseline, end of infusion, hour 2 and hour 4.
Arm 2: Limited pharmacokinetic (PK) testing of ACR-368 in combination with ULDG in all participants in Phase 1b	Dose of ACR-368 at day 1 and day 15 of first cycle	Cmax will be assessed in the first cycle at baseline, end of infusion, hour 2 and hour 4.
Overall Survival (OS)	Up to 2 years	The time from baseline 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 baseline until second disease progression or death whichever occurs first.

Trial Locations

Locations (67)

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

University of Massachusetts Chan Medical School; 🇺🇸 Worcester, Massachusetts, United States

Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

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

UC Irvine Health; 🇺🇸 Orange, California, United States

Stanford Cancer Center; 🇺🇸 Palo Alto, California, United States

University of California, Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

University of California Los Angeles (UCLA); 🇺🇸 Santa Monica, California, United States

University of Colorado; 🇺🇸 Aurora, Colorado, United States

Yale Cancer Center; 🇺🇸 New Haven, Connecticut, United States

Florida Gynecologic Oncology/Regional Cancer Center; 🇺🇸 Fort Myers, Florida, United States

Mount Sinai Comprehensive Cancer Center; 🇺🇸 Miami Beach, Florida, United States

Emory University; 🇺🇸 Atlanta, Georgia, United States

Northeast Georgia Medical Center; 🇺🇸 Gainesville, Georgia, United States

Northwestern Medicine; 🇺🇸 Chicago, Illinois, United States

University of Illinois Cancer Center; 🇺🇸 Chicago, Illinois, United States

University of Chicago Medicine; 🇺🇸 Chicago, Illinois, United States

Carle Cancer Center; 🇺🇸 Urbana, Illinois, United States

New York Presbyterian Hospital-Columbia University Medical Center; 🇺🇸 New York, New York, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

LSU Health Sciences; 🇺🇸 New Orleans, Louisiana, United States

American Oncology Partners of Maryland PA; 🇺🇸 Bethesda, Maryland, United States

National Institutes of Health, Clinical Center; 🇺🇸 Bethesda, Maryland, United States

Trials365, LLC; 🇺🇸 Shreveport, Louisiana, United States

Holy Cross Hospital; 🇺🇸 Silver Spring, Maryland, United States

HCA Midwest; 🇺🇸 Kansas City, Missouri, United States

John Theurer Cancer Center at Hackensack University Medical Center; 🇺🇸 Hackensack, New Jersey, United States

Memorial Sloan-Kettering Cancer Center; 🇺🇸 New York, New York, United States

Rutgers Cancer Institute of NJ; 🇺🇸 New Brunswick, New Jersey, United States

Laura & Isaac Perlmutter Cancer Center; 🇺🇸 New York, New York, United States

Mount Sinai Health System; 🇺🇸 New York, New York, United States

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

University of Cincinnati Cancer Center; 🇺🇸 Cincinnati, Ohio, United States

University of Rochester Medical Center; 🇺🇸 Rochester, New York, United States

Oncology Associates of Oregon; 🇺🇸 Eugene, Oregon, United States

FirstHealth of the Carolinas; 🇺🇸 Pinehurst, North Carolina, United States

Gabrail Cancer Center; 🇺🇸 Canton, Ohio, United States

Miami Valley Hospital South; 🇺🇸 Centerville, Ohio, United States

Stephenson Cancer Center at OU Health; 🇺🇸 Oklahoma City, Oklahoma, United States

Oregon Health & Sciences University; 🇺🇸 Portland, Oregon, United States

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Women & Infants Hospital; 🇺🇸 Providence, Rhode Island, United States

Ohio State University; 🇺🇸 Hilliard, Ohio, United States

West Penn Hospital; 🇺🇸 Pittsburgh, Pennsylvania, United States

Texas Oncology-Dallas Presbyterian Hospital; 🇺🇸 Dallas, Texas, United States

Sanford Health; 🇺🇸 Sioux Falls, South Dakota, United States

University of Texas Southwestern Medical Center; 🇺🇸 Dallas, Texas, United States

Huntsman Cancer Institute, University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Texas Oncology; 🇺🇸 Fort Worth, Texas, United States

University of Texas, MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

University of Virginia Health System; 🇺🇸 Charlottesville, Virginia, United States

Virginia Commonwealth University; 🇺🇸 Richmond, Virginia, United States

Swedish Cancer Center; 🇺🇸 Seattle, Washington, United States

Fred Hutchinson Cancer Center; 🇺🇸 Seattle, Washington, United States

Providence Sacred Heart Medical Center and Children's Hospital; 🇺🇸 Spokane, Washington, United States

Northwest Cancer Specialists, P.C.; 🇺🇸 Vancouver, Washington, United States

Froedtert and Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States