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

• ClinicalTrials.gov Identifier: NCT05548296
• Recruitment Status: Recruiting
• First Posted: September 21, 2022
• Last Update Posted: May 19, 2023
• Sponsor: Acrivon Therapeutics
• Collaborator: GOG Foundation
• Information provided by (Responsible Party): Acrivon Therapeutics

Study Description

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 low dose gemcitabine in participants with platinum-resistant ovarian carcinoma, endometrial adenocarcinoma, and urothelial carcinoma based on Acrivon's OncoSignature® test status.

Condition or disease	Intervention/treatment	Phase
Platinum-resistant Ovarian Cancer; Endometrial Adenocarcinoma; Urothelial Carcinoma	Drug: ACR-368; Drug: Gemcitabine; Diagnostic Test: OncoSignature	Phase 1; Phase 2

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 or Unevaluable tumors

Participants in Arm 1 will receive ACR-368 as monotherapy. Participants in Arm 2 will receive the combination of ACR-368 and low-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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 333 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• 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 a Phase 1b study to assess the safety of the combination of ACR-368 and escalating doses of low dose gemcitabine (LDG) in each of the 3 tumor types. When the recommended Phase 2 (RP2D) dose is determined, participants will be entered in an exploratory Phase 2 study to assess the efficacy and safety of ACR-368 and the RP2D of LDG in each of the 3 tumor types.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: August 29, 2022
• Estimated Primary Completion Date: July 31, 2026
• Estimated Study Completion Date: December 31, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: OncoSignature Positive Tumors; 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).	Drug: ACR-368; ACR-368 is an experimental drug; Other Name: prexasertib; Diagnostic Test: OncoSignature; Biomarker profile based on prediction of drug sensitivity performed on biopsy tissue
Experimental: OncoSignature Negative or Unevaluable test; In Arm 2, participants with an OncoSignature Negative or Unevaluable test will receive the combination of ACR-368 and Low Dose Gemcitabine (LDG). The Phase 1b portion will allow participants with OncoSignature Negative or Unevaluable tumors to be enrolled, while the Phase 2 portion will only enroll participants with OncoSignature Negative tumors. A Phase 1b Study will assess the safety of the combination of ACR-368 and escalating doses of LDG 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 LDG. When determined, a Phase 2 Exploratory Study will be initiated to assess the efficacy and safety of the combination of ACR-368 and the RP2D of LDG in each of the 3 cohorts of participants (ovarian, endometrial, and urothelial).	Drug: ACR-368; ACR-368 is an experimental drug; Other Name: prexasertib; Drug: Gemcitabine; Gemcitabine is a standard of care given at a low dose in combination with the experimental drug ACR-368; Diagnostic Test: OncoSignature; Biomarker profile based on prediction of drug sensitivity performed on biopsy tissue

Outcome Measures

Primary Outcome Measures :

1. Arm 1 Monotherapy: Anti-tumor activity of ACR-368 in Ovarian, Endometrial, and Urothelial Cohorts [ Time Frame: 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.
2. Arm 2 Phase 1b: Adverse Events (AEs) for ACR-368 in combination with LDG [ Time Frame: 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.
3. Arm 2 Phase 1b: Determine the RP2D of LDG [ Time Frame: AEs will be assessed from first dose of LDG for 28 days for each subject in a cohort. ]
   The RP2D will be evaluated by the incidence of DLT events per dose level
4. Arm 2 Exploratory Phase 2: Anti-tumor activity of ACR-368 plus LDG in Ovarian, Endometrial and Urothelial Cohorts [ Time Frame: 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 :

1. Arm 1: Number of subjects with confirmed OncoSignature thresholds for enrichment of ACR-368 monotherapy responders [ Time Frame: 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
2. Arm 1: Adverse Events (AEs) for ACR-368 monotherapy [ Time Frame: 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.
3. Relative dose intensity of ACR-368 [ Time Frame: 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
4. Arm 1: Limited pharmacokinetic (PK) testing in participants with Ovarian Carcinoma [ Time Frame: 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
5. Arm 2: Limited pharmacokinetic (PK) testing of ACR-368 in combination with LDG in all participants in Phase 1b [ Time Frame: 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
6. Overall Survival (OS) [ Time Frame: Up to 2 years ]
   The time from baseline until date of death
7. Duration of Response (DOR) [ Time Frame: Up to 2 years ]
   The time from initial response until investigator assessed progressive disease for all subjects who achieve a confirmed objective response.
8. Progression-free Survival (PFS) [ Time Frame: Up to 2 years ]
   The time from baseline until second disease progression or death whichever occurs first.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criterial: General

1. Participants who are 18 years of age or older at time of consent.
2. Participant must be able to give signed, written informed consent.
3. Participant must have histologically confirmed, locally advanced (ie, not amenable to curative surgery and/or radiation therapy) or metastatic cancer that has progressed during or after at least 1 prior therapeutic regimen.
4. 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.
5. Participant must be willing to provide tissue from a newly obtained tumor biopsy from an accessible tumor lesion not previously irradiated. Newly obtained is defined as a specimen obtained up to 12 weeks prior to initiation of treatment on Day 1 if no intercurrent systemic therapy in the interval. For biopsies obtained prior to the signing of the consent, Investigators should contact the Medical Monitor to confirm sample will be acceptable.
6. Participant must be willing to provide an archival tumor tissue block or at least 20 unstained slides, if available.
7. 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.
8. Participant must have an Eastern Cooperative Oncology Group Performance Status 0 or 1.
9. Participant must have an estimated life expectancy of longer than 3 months.
10. 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.
11. Participant must have adequate coagulation profile as defined below (including if receiving anticoagulation therapy): Prothrombin time within the ULN. Activated partial thromboplastin time within the 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. Primary platinum refractory disease, defined as progression while on the upfront platinum-based therapy, is not 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) immunotherapy as single agent or in combination with lenvatinib 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:

   a. Endocrine events from prior immunotherapy at Grade > 2. b. Neuropathy events from prior cytotoxic therapies at Grade > 2. c. 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.
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.

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.

Contacts and Locations

Contacts

Contact: Dominic Lai, MD; 617-207-8976; ACR-368-201ClinicalTrial@acrivon.com

Contact: Jeanie Tang; ACR-368-201ClinicalTrial@acrivon.com

Locations

United States, Alabama

University of South Alabama Mitchell Cancer Institute; Recruiting

Mobile, Alabama, United States, 36604

Contact: Stafanie White

Principal Investigator: Jennifer Scalici, MD

United States, California

City of Hope National Medical Center; Recruiting

Duarte, California, United States, 91010

Contact: Lorna Rodriguez, MD

Principal Investigator: Mihae Song, MD

Hoag Cancer Center; Recruiting

Newport Beach, California, United States, 92663

Contact: Esmerelda Martinez

Principal Investigator: Alberto Mendivil, MD

United States, Connecticut

Yale Cancer Center; Recruiting

New Haven, Connecticut, United States, 06520

Contact: Ingrid Palma

Principal Investigator: Joseph W. Kim, MD

United States, Florida

Florida Gynecologic Oncology/Regional Cancer Center; Recruiting

Fort Myers, Florida, United States, 33905

Contact: Samith Sandadi

Principal Investigator: Edward Grendys, MD

Mount Sinai Comprehensive Cancer Center; Recruiting

Miami Beach, Florida, United States, 33140

Contact: Ana Lacombe

Principal Investigator: Brian Slomovitz, MD

United States, Illinois

Northwestern Medicine; Recruiting

Chicago, Illinois, United States, 60611

Contact: Jack Burrows

Principal Investigator: Daniela Matei, MD

United States, Louisiana

Trials365, LLC; Recruiting

Shreveport, Louisiana, United States, 71103

Contact: Carrie Kay

Principal Investigator: Destin Black, MD

United States, Maryland

American Oncology Partners of Maryland PA; Recruiting

Bethesda, Maryland, United States, 20817

Contact: Natalie Bongiorno

Principal Investigator: Mark Goldstein, MD

National Institutes of Health, Clinical Center; Recruiting

Bethesda, Maryland, United States, 20892

Contact: Ann McCoy, RN

Principal Investigator: Jung-Min Lee, MD

Holy Cross Hospital; Recruiting

Silver Spring, Maryland, United States, 20910

Contact: Sujana Lalagari

Principal Investigator: James F Barter, MD

United States, Michigan

Karmanos Cancer Institute; Recruiting

Detroit, Michigan, United States, 48201

Contact: Robert Morris, MD, PhD

Principal Investigator: Ira Winer, MD, PhD

United States, Missouri

HCA Midwest; Recruiting

Kansas City, Missouri, United States, 64132

Contact: Megan Werner

Principal Investigator: Kristopher LyBarger, DO

United States, New Jersey

John Theurer Cancer Center at Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

Contact: Lauren Wiest

Principal Investigator: Donna McNamara, MD

United States, New York

Laura & Isaac Perlmutter Cancer Center; Recruiting

New York, New York, United States, 10016

Contact: Karen Estok

Principal Investigator: Bhavana Pothuri, MD

Memorial Sloan-Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

Contact: Chrisann Kyi, MD

Principal Investigator: Jonathan Rosenberg, MD

United States, North Carolina

FirstHealth of the Carolinas; Recruiting

Pinehurst, North Carolina, United States, 28374

Contact: Pamela Mason

Principal Investigator: Michael J. Sundborg, MD

United States, Ohio

Gabrail Cancer Center; Recruiting

Canton, Ohio, United States, 44718

Contact: Kim Roby

Principal Investigator: Nashat Gabrail, MD

Miami Valley Hospital South; Recruiting

Centerville, Ohio, United States, 45459

Contact: Rebecca Wirth

Principal Investigator: Michael Guy, MD

United States, Oklahoma

Stephenson Cancer Center at OU Health; Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contact phase1-referrals@ouhsc.edu

Principal Investigator: Debra Richardson, MD

United States, Rhode Island

Women & Infants Hospital; Recruiting

Providence, Rhode Island, United States, 02905

Contact oncologyresearch@wihri.org

Principal Investigator: Cara Mathews, MD

United States, South Dakota

Sanford Health; Recruiting

Sioux Falls, South Dakota, United States, 57104

Contact: Ashley Johnson

Principal Investigator: Maria Bell, MD

United States, Texas

University of Texas, MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Nicholas Hanan

Principal Investigator: Funda Meric-Bernstam, MD

United States, Washington

Summit Cancer Center; Recruiting

Spokane, Washington, United States, 99208

Contact: Monika Chaudhry

Contact: Monika

Principal Investigator: Arvind Chaudhry, MD, PhD

Sponsors and Collaborators

Acrivon Therapeutics

GOG Foundation

Investigators

• Principal Investigator: Jung-Min Lee, MD; National Cancer Institute (NCI)

More Information

• Responsible Party: Acrivon Therapeutics
• ClinicalTrials.gov Identifier: NCT05548296
• Other Study ID Numbers: ACR-368-201 (GOG 3082)
• First Posted: September 21, 2022
• Last Update Posted: May 19, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

Keywords provided by Acrivon Therapeutics:

Urothelial Carcinoma; Bladder Cancer; Urinary Bladder Neoplasm; Urologic Neoplasm; Urogenital Neoplasm; Endometrial Cancer; Endometrial Neoplasm; Ovarian Cancer; Ovarian Neoplasm; Low dose gemcitabine; Platinum-resistant Ovarian Carcinoma

Additional relevant MeSH terms:

Carcinoma; Adenocarcinoma; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Carcinoma, Transitional Cell; Uterine Neoplasms; Endometrial Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Uterine Diseases; Gemcitabine; Prexasertib; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents