Clinical trial NCT05548296: A Study of ACR-368 in Ovarian Carcinoma, Endometrial Adenocarcinoma, and Urothelial Carcinoma
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Platinum-resistant Ovarian Cancer
Endometrial Adenocarcinoma
Urothelial Carcinoma
Keywords: Urothelial Carcinoma
Bladder Cancer
Urinary Bladder Neoplasm
Urologic Neoplasm
Urogenital Neoplasm
Endometrial Cancer
Endometrial Neoplasm
Ovarian Cancer
Ovarian Neoplasm
Ultralow dose gemcitabine
Platinum-resistant Ovarian Carcinoma
Lead sponsor: Acrivon Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: GOG Foundation
First posted: 2022-09-21
Enrollment: 390
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants with an OncoSignature positive test will enter a Phase 2 study that will assess the efficacy of ACR-368 as monotherapy in each of the 3 tumor types, ovarian, endometrial, and urothelial carcinomas. Participants with an OncoSignature negative test will be entered in an exploratory Phase 2 study to assess the efficacy and safety of the combination of ACR-368 and ultralow dose gemcitabine (ULDG) in each of the 3 tumor types.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Arm 1 Monotherapy: Anti-tumor activity of ACR-368 in Ovarian, Endometrial, and Urothelial Cohorts
timeFrame: Response will be assessed every 8 weeks from baseline through 2 years or death.
measure: Arm 2 Phase 1b: Adverse Events (AEs) for ACR-368 in combination with ULDG
timeFrame: AEs will be assessed from baseline through 2 years or death.
measure: Arm 2 Phase 1b: Determine the RP2D of ULDG
timeFrame: AEs will be assessed from first dose of ULDG for 28 days for each subject in a cohort.
measure: Arm 2 Exploratory Phase 2: Anti-tumor activity of ACR-368 plus ULDG in Ovarian, Endometrial and Urothelial Cohorts
timeFrame: Response will be assessed every 8 weeks from baseline through 2 years or death.
Secondary outcomes:
measure: Arm 1: Number of subjects with confirmed OncoSignature thresholds for enrichment of ACR-368 monotherapy responders
timeFrame: Baseline to first post treatment imaging at 8 weeks
measure: Arm 1: Adverse Events (AEs) for ACR-368 monotherapy
timeFrame: AEs will be assessed from baseline through 2 years or death.
measure: Relative dose intensity of ACR-368
timeFrame: First dose of ACR-368 in first cycle to dose on day 15 of second cycle of administration.
measure: Arm 1: Limited pharmacokinetic (PK) testing in participants with Ovarian Carcinoma
timeFrame: Dose of ACR-368 at day 1 and day 15 of first cycle
measure: Arm 2: Limited pharmacokinetic (PK) testing of ACR-368 in combination with ULDG in all participants in Phase 1b
timeFrame: Dose of ACR-368 at day 1 and day 15 of first cycle
measure: Overall Survival (OS)
timeFrame: Up to 2 years
measure: Duration of Response (DOR)
timeFrame: Up to 2 years
measure: Progression-free Survival (PFS)
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama Mitchell Cancer Institute
state: Alabama
city: Anchorage
country: United States
facility: Alaska Women's Cancer Center
state: Alaska
city: Phoenix
country: United States
facility: HonorHealth
state: Arizona
city: Tucson
country: United States
facility: Arizona Oncology Associate, PC- HOPE
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Newport Beach
country: United States
facility: Hoag Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Health
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California, Davis Comprehensive Cancer Center
state: California
city: Santa Monica
country: United States
facility: University of California Los Angeles (UCLA)
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Fort Myers
country: United States
facility: Florida Gynecologic Oncology/Regional Cancer Center
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern Medicine
state: Illinois
city: Chicago
country: United States
facility: University of Illinois Cancer Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: New Orleans
country: United States
facility: LSU Health Sciences
state: Louisiana
city: Shreveport
country: United States
facility: Trials365, LLC
state: Louisiana
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland PA
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health, Clinical Center
state: Maryland
city: Silver Spring
country: United States
facility: Holy Cross Hospital
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Chan Medical School
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Kansas City
country: United States
facility: HCA Midwest
state: Missouri
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of NJ
state: New Jersey
city: New York
country: United States
facility: Laura & Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital-Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai Health System
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Pinehurst
country: United States
facility: FirstHealth of the Carolinas
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Centerville
country: United States
facility: Miami Valley Hospital South
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Hilliard
country: United States
facility: Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center at OU Health
state: Oklahoma
city: Eugene
country: United States
facility: Oncology Associates of Oregon
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: West Penn Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Women & Infants Hospital
state: Rhode Island
city: Sioux Falls
country: United States
facility: Sanford Health
state: South Dakota
city: Dallas
country: United States
facility: Texas Oncology-Dallas Presbyterian Hospital
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology
state: Texas
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Center
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Washington
city: Milwaukee
country: United States
facility: Froedtert and Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: National Cancer Institute (NCI)
name: Jung-Min Lee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan-Kettering Cancer Center (MSKCC)
name: Jonathan Rosenberg, MD
role: PRINCIPAL_INVESTIGATOR
References: