This study is NOT currently recruiting participants.
Carcinoma is a type of cancer that starts in cells that make up the skin or the tissue that lines organs and glands. These include cancers of the ovaries (ovarian carcinoma); the lining of the womb (endometrial adenocarcinoma); and the bladder (urothelial carcinoma). These cancers often return after the first round of treatment, and survival rates are very low. Better treatments are needed.
To test a study drug (ACR-368), used alone or combined with an approved drug (low dose gemcitabine, or LDG).
People aged 18 years and older who have ovarian, endometrial, or urothelial cancer.
Participants will be screened. They will have a physical exam and a test of heart function. They will give blood and urine samples. They will have an imaging scan. They will have a biopsy (tissue sample) of their tumor.
Participants will be assigned to 1 of 2 groups.
ACR-368 is administered intravenously, that is, through a tube attached to a needle inserted into a vein in the arm. Each treatment takes about 60 minutes. The drug will be given once every 14 days to all participants.
Participants in the second group will also receive LDG. LDG is also administered intravenously, over about 60 minutes. Every 14 days, these participants will receive the LDG first; then, after a 3-hour wait, they will receive the ACR-368.
Imaging scans, blood sampling, and other tests may also be done during treatment visits.
Participants may remain in the study as long as they are benefiting from treatment.
INCLUSION CRITERIA:
1. Subjects who are 18 years of age or older at time of consent.
2. Subject must be able to give signed, written informed consent.
3. Subject must have histologically documented, high-grade endometrial cancer:
-All Grade 3 International Federation of Gynecology and Obstetrics epithelial endometrial histological subtypes are eligible including: endometrioid (Grade 3 only), serous, carcinosarcomas, clear-cell carcinoma, and mixed histologies.
4. Treatment history requirements:
Arms 1 and 2:
-Subject must have received prior platinum-based chemotherapy.
-Subject must have received prior anti-PD-(L)1 therapy.
-Subject must not have received more than three lines of any type of prior systemic therapy (capped)
-The proportion of subjects who progressed during the first 12 weeks of last prior line of therapy is capped and currently not being enrolled
Arm 3 only:
-Subject must have received prior platinum-based chemotherapy.
-Subject must have received prior anti-PD-(L)1 therapy.
-Subject must not have received more than one line of any type of prior systemic therapy.
-Subject must not have progressed during first 12 weeks of the anticancer therapy.
Note for all arms:
-For subjects with HER2 3+ tumor(s), the subject must have received trastuzumab deruxtecan (T-DXd). This line of therapy does not count towards the prior lines of therapy.
-A maximum of one prior line of anti-PD-(L)1 therapy is permitted, delivered with a chemotherapy or as single agent or with lenvatinib.
-Prior surgery, prior adjuvant therapy given for high-risk early-stage disease, prior hormonal therapy, and prior radiation therapy are allowed and do not count as prior lines of therapy.
-Neo-adjuvant therapy for primary advanced disease is counted as a line of therapy.
5. Subject must have histologically confirmed metastatic cancer that has progressed during or after at least 1 prior therapeutic regimen. Confirmation of progression must be established using a set of imaging that will also be used to determine the presence of at least one measurable lesion (all subjects), and of a lesion that can be biopsied (only for subjects in the OncoSignature Selection Cohort). Imaging collected before the inclusion in the study are acceptable to determine eligibility and to guide the biopsy.
6. Subject must have at least 1 measurable lesion per RECIST v1.1 criteria (by local Investigator). Subject must have radiographic evidence of disease progression based on RECIST v1.1 criteria following the most recent line of treatment. Subjects will be eligible to start the study treatment only in the presence of a baseline tumor imaging that has been obtained within 28 days of the treatment start. Subjects with baseline imaging that is more than 28 days will not be eligible to receive the study treatment unless the tumor baseline imaging is repeated.
7. Arms 1 and 2 only: Subject 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. Tumor biopsy tissue should be collected with the largest needle safely possible in accordance with the Laboratory Manual. Ideally, 3 core biopsies should be collected and immediately put in Sponsor-provided 10% neutral buffered formalin (NBF) vials, labelled "GoPath", and returned to Sponsor's tissue processing laboratory (GoPath) to ensure uniform biopsy processing and avoidance of eosin during tissue processing. A lesion used for biopsy cannot be used as a measurable lesion.
8. Subject must be willing to provide archival tumor, either as a tissue block or at least 20 unstained slides, if available.
9. Subject must be willing to remain in the clinic until the completion of all study-related subject procedures (eg, 4 hours pharmacokinetic [PK] blood draw post-infusion on Day 1).
10. Subject 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.
11. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
12. Subject must have an estimated life expectancy of longer than 3 months.
13. Subject must have adequate organ function at Screening, defined as:
-Absolute neutrophil count > 1500 cells/microL without growth factor support within 1 week prior to
obtaining the hematology values at Screening.
-Hemoglobin >= 9.0 g/dL.
-Platelets >= 150,000 cells/microL without transfusion within 1 week prior to obtaining the hematology values at Screening.
-Calculated creatinine clearance (CrCl) >= 50 mL/min as calculated by the Cockcroft-Gault formula.
-Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 3 x upper limit of normal (ULN); <= 5 x ULN if liver metastases are present.
-Total bilirubin <= 1.5 x ULN not associated with Gilbert's syndrome. If associated with Gilbert's syndrome <= 3 x ULN is acceptable.
-Serum albumin >= 3 g/dL.
14. Subject 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 anticoagulant for >= 1 month:
-Prothrombin time within 1.5 x the ULN, and
-Activated partial thromboplastin time within 1.5 x the ULN.
15. Subjects must be non-lactating.
16. Women of childbearing potential (WOCBP) must agree to use a highly effective contraceptive method while on ACR-368 and for at least 7 months after the last dose.
17. WOCBP must have a negative pregnancy test prior to the newly obtained pretreatment tumor biopsy and within 48 hours prior to dosing of study drug.
18. Subject is willing and able to comply with clinical trial instructions and requirements.
EXCLUSION CRITERIA:
A subject will be excluded from the study if any of the following criteria apply:
1. Subject with known symptomatic brain metastases requiring > 10 mg/day of prednisolone (or its equivalent). Subjects 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. Subject has low-grade (Grade 1 & 2) endometrioid carcinoma.
3. Subject has mesenchymal tumors of the uterus.
4. Subject has a history of clinically meaningful ascites, defined as a history of paracentesis or thoracentesis with therapeutic intent, within 4 weeks of Screening. Subjects with planned therapeutic paracentesis or thoracentesis between Screening and Cycle 1 Day 1 dosing are excluded.
5. Subject had systemic therapy or radiation therapy within 3 weeks prior to the first dose of study drug.
6. Subjects who had a longer platinum-free interval (>12 months) after carboplatin-paclitaxel and are deemed by Investigator to be eligible for carboplatin-paclitaxel re-challenge are excluded from this study.
7. Subjects has known human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is considered uncontrolled.
8. Subject has a history of clinically meaningful coagulopathy, bleeding diathesis.
9. Subject has cardiovascular disease, defined as:
-Uncontrolled hypertension defined as blood pressure > 160/90 mmHg at Screening confirmed by repeat (medication permitted).
-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).
-Symptomatic heart failure (per New York Heart Association guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction < 20%, transient ischemic attack, or cerebrovascular accident within 6 months of Day 1).
10. Subject has a history of major surgery within 4 weeks of Screening.
11. Subject has bowel obstruction related to the current cancer within the last 6 months or 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.
12. Subject has taken a prior cell cycle Checkpoint Kinase 1 (CHK1) inhibitor, including ACR-368.
13. Women who are pregnant or lactating.
14. Subject has a history of other malignancy within 2 years prior to enrollment. Note: Subjects with tumors with a negligible risk for metastasis or death (including, but not limited to, adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix or breast) are eligible.
15. Subject has active infection requiring systemic antibiotics.