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

Urothelial Carcinoma Clinical Trial

Official title:

A Phase 1b/2 Basket Study of ACR-368 as Monotherapy and in Combination With Gemcitabine in Adult Subjects With Platinum-Resistant Ovarian Carcinoma, Endometrial Adenocarcinoma, and Urothelial Carcinoma Based on Acrivon OncoSignature® Status

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05548296
• Other study ID #: ACR-368-201 (GOG 3082)
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 29, 2022
• Est. completion date: December 31, 2027

Study information

• Verified date: May 2024
• Source: Acrivon Therapeutics
• Contact: Jean-Marie Cuillerot, MD
• Phone: 617-207-8976
• Email: ACR-368-201ClinicalTrial[@]acrivon.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 390
• Est. completion date: December 31, 2027
• Est. primary completion date: July 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criterial: 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 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria (by local Investigator) (Eisenhauer, 2009). Participant must have radiographic evidence of disease progression based on RECIST criteria following the most recent line of treatment. Biochemical recurrence (eg, 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 signed informed consent. Newly obtained is defined as a specimen obtained up to 6 weeks prior to initiation of treatment on Day 1 if no intercurrent systemic therapy in the interval.

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:

• 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.

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:

• 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 without transfusion or growth factor support within 2 weeks prior to obtaining the hematology values at Screening.
• Platelets = 100,000 cells/µL without transfusion within 1 week prior to obtaining the hematology values at Screening.
• Calculated creatinine clearance = 30 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.

10. Participant must have adequate coagulation profile as defined below (including if receiving anticoagulation therapy): Prothrombin time within 1.5 x ULN. Activated partial thromboplastin time within 1.5 x ULN. If the patient is anticoagulated, must be on a stable dose of anticoagulant for = 1 month. Tumor Specific Inclusion Criteria

For Ovarian Carcinoma:

1. Participant must have histologically documented, platinum resistant, advanced (metastatic and/or unresectable) high-grade serous/endometrioid ovarian, primary peritoneal, or fallopian tube cancer. Platinum-resistant disease, defined as progression or relapse within 6 months after the completion of platinum-based therapy, is eligible. Platinum sensitive disease, defined as disease which progress after 6 or more months after the completion of platinum-based therapy and primary platinum refractory disease, defined as progression while on the upfront platinum-based therapy, is not eligible. 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). 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 histologies are eligible including: endometrioid, serous, and clear-cell carcinoma.

2. Carcinosarcoma is eligible. Enrollment of participants with this histology will be capped at 5% for each cohort.

3. Participant must have no more than 3 prior lines of therapy in the recurrent setting, including platinum-based chemotherapy for subtypes of endometrial adenocarcinoma where it is a standard of care.

2. Participant must have documented failure or ineligibility (based on Investigator judgement) for prior anti-programmed cell death protein 1/anti-programmed death- ligand 1 (PD 1/PD L1) based therapy for advanced/metastatic disease. Prior combination of PD 1/PD L1 inhibitor and vascular endothelial growth factor tyrosine kinase inhibitor is acceptable. 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. Failed or have been ineligible for checkpoint inhibitors (including PD-1 or PD-L1 inhibitors).

3. Failed or have been ineligible for enfortumab vedotin.

4. Have no known life-prolonging therapy available 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 a failure to recover from the reversible effects of prior anti-cancer

therapy, as follows:

1. Endocrine events from prior immunotherapy at Grade > 2.

2. Neuropathy events from prior cytotoxic therapies at Grade > 2.

3. All other reversible effects of prior anti- cancer therapy (except alopecia) at Grade >1 or Baseline.

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

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

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

6. 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 (QTc) > 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).

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

8. Participant has a history of bowel obstruction requiring decompression through a nasogastric tube within 8 weeks of Screening. Participants has signs or symptoms of intestinal obstruction, which include nausea, vomiting, and objective radiologic finding of bowel obstruction.

9. 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.

Related Conditions & MeSH terms

• Adenocarcinoma
• Carcinoma
• Carcinoma, Ovarian Epithelial
• Carcinoma, Transitional Cell
• Endometrial Adenocarcinoma
• Endometrial Neoplasms
• Ovarian Neoplasms
• Platinum-resistant Ovarian Cancer
• Urothelial Carcinoma
• Uterine Neoplasms

Intervention

Drug:
• ACR-368
ACR-368 is an experimental drug
• Gemcitabine
Gemcitabine is a standard of care given at ultralow dose in combination with the experimental drug ACR-368

Diagnostic Test:
• OncoSignature
Biomarker profile based on prediction of drug sensitivity performed on biopsy tissue

Locations

Country	Name	City	State
United States	Alaska Women's Cancer Center	Anchorage	Alaska
United States	Emory University	Atlanta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	American Oncology Partners of Maryland PA	Bethesda	Maryland
United States	National Institutes of Health, Clinical Center	Bethesda	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Gabrail Cancer Center	Canton	Ohio
United States	Miami Valley Hospital South	Centerville	Ohio
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Northwestern Medicine	Chicago	Illinois
United States	University of Chicago Medicine	Chicago	Illinois
United States	University of Illinois Cancer Center	Chicago	Illinois
United States	University of Cincinnati Cancer Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Texas Oncology-Dallas Presbyterian Hospital	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	Oncology Associates of Oregon	Eugene	Oregon
United States	Florida Gynecologic Oncology/Regional Cancer Center	Fort Myers	Florida
United States	Texas Oncology	Fort Worth	Texas
United States	Northeast Georgia Medical Center	Gainesville	Georgia
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Ohio State University	Hilliard	Ohio
United States	University of Texas, MD Anderson Cancer Center	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	HCA Midwest	Kansas City	Missouri
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	USC/Norris Comprehensive Cancer Center	Los Angeles	California
United States	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida
United States	Froedtert and Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama
United States	Rutgers Cancer Institute of NJ	New Brunswick	New Jersey
United States	Yale Cancer Center	New Haven	Connecticut
United States	LSU Health Sciences	New Orleans	Louisiana
United States	Laura & Isaac Perlmutter Cancer Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mount Sinai Health System	New York	New York
United States	New York Presbyterian Hospital-Columbia University Medical Center	New York	New York
United States	Hoag Cancer Center	Newport Beach	California
United States	Stephenson Cancer Center at OU Health	Oklahoma City	Oklahoma
United States	UC Irvine Health	Orange	California
United States	Stanford Cancer Center	Palo Alto	California
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	HonorHealth	Phoenix	Arizona
United States	FirstHealth of the Carolinas	Pinehurst	North Carolina
United States	West Penn Hospital	Pittsburgh	Pennsylvania
United States	Oregon Health & Sciences University	Portland	Oregon
United States	Women & Infants Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of Rochester Medical Center	Rochester	New York
United States	University of California, Davis Comprehensive Cancer Center	Sacramento	California
United States	Huntsman Cancer Institute, University of Utah	Salt Lake City	Utah
United States	University of California Los Angeles (UCLA)	Santa Monica	California
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Swedish Cancer Center	Seattle	Washington
United States	Trials365, LLC	Shreveport	Louisiana
United States	Holy Cross Hospital	Silver Spring	Maryland
United States	Sanford Health	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Summit Cancer Center	Spokane	Washington
United States	Arizona Oncology Associate, PC- HOPE	Tucson	Arizona
United States	Carle Cancer Center	Urbana	Illinois
United States	Northwest Cancer Specialists, P.C.	Vancouver	Washington
United States	University of Massachusetts Chan Medical School	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Acrivon Therapeutics	GOG Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Arm 1 Monotherapy: Anti-tumor activity of ACR-368 in Ovarian, Endometrial, and Urothelial Cohorts	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.	Response will be assessed every 8 weeks from baseline through 2 years or death.
Primary	Arm 2 Phase 1b: Adverse Events (AEs) for ACR-368 in combination with ULDG	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.	AEs will be assessed from baseline through 2 years or death.
Primary	Arm 2 Phase 1b: Determine the RP2D of ULDG	The RP2D will be evaluated by the incidence of DLT events per dose level	AEs will be assessed from first dose of ULDG for 28 days for each subject in a cohort.
Primary	Arm 2 Exploratory Phase 2: Anti-tumor activity of ACR-368 plus ULDG in Ovarian, Endometrial and Urothelial Cohorts	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.	Response will be assessed every 8 weeks from baseline through 2 years or death.
Secondary	Arm 1: Number of subjects with confirmed OncoSignature thresholds for enrichment of ACR-368 monotherapy responders	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	Baseline to first post treatment imaging at 8 weeks
Secondary	Arm 1: Adverse Events (AEs) for ACR-368 monotherapy	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.	AEs will be assessed from baseline through 2 years or death.
Secondary	Relative dose intensity of ACR-368	Assess the ratio of cumulative administered dose to the planned dose for first 2 cycles	First dose of ACR-368 in first cycle to dose on day 15 of second cycle of administration
Secondary	Arm 1: Limited pharmacokinetic (PK) testing in participants with Ovarian Carcinoma	Cmax will be assessed in the first cycle at baseline, end of infusion, hour 2 and hour 4	Dose of ACR-368 at day 1 and day 15 of first cycle
Secondary	Arm 2: Limited pharmacokinetic (PK) testing of ACR-368 in combination with ULDG in all participants in Phase 1b	Cmax will be assessed in the first cycle at baseline, end of infusion, hour 2 and hour 4	Dose of ACR-368 at day 1 and day 15 of first cycle
Secondary	Overall Survival (OS)	The time from baseline until date of death	Up to 2 years
Secondary	Duration of Response (DOR)	The time from initial response until investigator assessed progressive disease for all subjects who achieve a confirmed objective response.	Up to 2 years
Secondary	Progression-free Survival (PFS)	The time from baseline until second disease progression or death whichever occurs first.	Up to 2 years

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