Study on ACR-368 for Treating Ovarian, Endometrial, and Bladder Cancers

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 Exclusions:

  • Patients with brain cancer that requires more than 10 mg/day of steroids.
  • Patients who have not recovered from side effects of previous cancer treatments.
  • Patients who have had other cancer treatments or radiation within two weeks before starting the study.
  • Patients with uncontrolled HIV, hepatitis B, or hepatitis C infections.
  • Patients with blood clotting disorders or significant heart problems.
  • Patients who have had major surgery within four weeks before the study.
  • Patients with recent bowel obstructions or certain bowel conditions.
  • Patients who have previously taken a drug similar to ACR-368.

• Specific Exclusions for Ovarian Cancer:

  • Patients with certain types of ovarian cancer, like clear-cell or low-grade serous carcinoma.
  • Patients with fluid buildup in the abdomen or chest that required drainage recently.
  • Patients with active inflammatory bowel disease or recent bowel issues.

• Specific Exclusions for Endometrial Cancer:

  • Patients with low-grade endometrial cancer or certain uterine tumors.
  • Patients with recent fluid buildup in the abdomen or chest.

• Specific Exclusions for Bladder Cancer:

  • Patients with certain types of bladder cancer, like sarcoma or melanoma.
  • Patients who have not received previous platinum-based chemotherapy.
  • Patients with small cell or neuroendocrine bladder cancer.