MC# 22-33 - Phase I/II Study of PRO1184 in Patients with Locally Advanced and/or Metastatic Solid Tumors
Disease Type(s): Breast, Endometrial, Mesothelioma, Ovarian, Lung-NSCLC
Phase(s): I, II
Drug Classification(s): Small Molecule, Targeted Therapy
Molecular Target(s): FRα
Mechanism of Action
PRO11841 is an antibody drug conjugate that is directed to folate molecules to bind to cells with folate receptor in order to deliver the attached cytotoxic payload molecules.
In this study, the sponsor and investigators want to learn:
- How much of PRO1184 can be given with an acceptable level of side effects
- The effects of PRO1184 (good and bad)
- How much of PRO1184 is absorbed into the blood and how fast it is removed
- Patients must have histologically or cytologically confirmed metastatic or unresectable solid malignancy within 1 of the tumor types listed below. Patients must have previously received all therapies known to confer clinical benefit (unless ineligible to receive or refused to receive or therapy is unavailable in the region). If a standard-of-care therapy is available that has not been administered, the reason that the therapy is not appropriate must be documented.
- Ovarian cancer (must have epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer)
- Endometrial cancer (any subtype excluding sarcoma and carcinosarcoma)
- Non-small cell lung cancer (NSCLC)
- Breast cancer (adenocarcinoma; HR+/HER2- and triple negative, excluding HER2+)
- Mesothelioma (any subtype, pleural or peritoneal)
- All patients should be willing to provide a pre-treatment tumor specimen (archival or fresh biopsy samples). If a fresh biopsy is required, procedures more invasive than a core biopsy or significant risk procedures forwhich the procedure-associated absolute risk of mortality or major morbidity in the patient’s clinical setting and specific institution is 2% or higher, should not be utilized.
- Patients enrolled in Part B, Dose Expansion, must have evidence of folate receptor alpha (FRα) expression in ≥25% of tumor cells with at least 1+ intensity by IHC in a tumor-related sample (archived or fresh) by a Sponsor-designated central laboratory. Documentation of a previous positive test with the Ventana FRα assay done as part of a clinical trial will be considered adequate for enrollment eligibility, and the patient’s tissue will still be collected for retrospective confirmation.
- Age 18 years or older.
- An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
- Measurable disease per the response evaluation criteria in solid tumors (RECIST) version 1.1 at baseline for all tumor types other than pleural mesothelioma which will use modified response evaluation criteria in solid tumors for assessment of response in malignant pleural mesothelioma (mRECIST) v1.1.
- Patients cannot receive supportive care for low platelets, neutrophils or hemoglobin 2 weeks prior to the screening period. The following baseline laboratory data is required:
- absolute neutrophil count (ANC) ≥1500/μL
- hemoglobin (Hgb) ≥9 g/dL
- platelet count ≥100,000/μL
- serum total bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for Patients with Gilbert’s disease
- creatinine clearance ≥60 mL/min
- alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN (≤5 × ULN if there is evidence of hepatic involvement by malignant disease)
- All toxicities related to prior radiotherapy, chemotherapy or surgical procedure must have recovered to baseline or Grade ≤ 1 based on CTCAE v 5.0 except alopecia, G2 peripheral neuropathy and AEs that are clinically nonsignificant or stable on supportive therapy.
- The patient must provide written informed consent.
- History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
- Known active central nervous system metastases. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry after brain metastasis treatment, they have no new or enlarging brain metastases, and are off corticosteroids and anticonvulsants prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of PRO1184. Patients with suspected brain metastases at Screening should undergo a CT/MRI of the brain prior to study entry. Baseline brain MRI is required for all NSCLC patients and triple negative breast cancer patients.
- Carcinomatous meningitis.
- Any uncontrolled ≥ Grade 3 (per the NCI CTCAE, Version 5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of PRO1184. Routine antimicrobial prophylaxis is permitted.
- Uncontrolled diabetes mellitus, defined as Hgb A1c) ≥8% or Hgb A1c between 7% and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
- Positive for hepatitis B by surface antigen expression. Active hepatitis C infection (positive by polymerase chain reaction [PCR] or on antiviral therapy for hepatitis C within the last 6 months). Patients who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
- Positive for human immunodeficiency virus (HIV).
- Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or congestive heart failure with symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of PRO1184.
- History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
- Prior antitumor treatments must have a washout period of 2 weeks for small molecules and 4 weeks for antibody-based therapeutics prior to first dose of study drug. If the underlying disease has progressed on treatment with antibody-based therapeutics, a washout period of 2 weeks prior to the first dose of study drug is acceptable.
- During dose escalation only, use of strong cytochrome P450 3A (CYP3A) inhibitors within 14 days of study drug dosing.
- Radiotherapy or major surgery that is not completed 2 weeks prior to the first dose of PRO1184.
- Patients of childbearing potential unless under the following conditions:
- Must have a negative serum pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of PRO1184. Patients with false positive results and documented verification that the patient is not pregnant are eligible for participation.
- Must agree not to try to become pregnant during the study and for at least 2 months after the final dose of study drug
- Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 2 months after the final dose of study drug
- If sexually active in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control starting at the time of informed consent and continuing throughout the study and for at least 2 months after the final dose of study drug
- Patients who can father children, unless under the following conditions:
- Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 4 months after the final dose of study drug.
- If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control starting at time of informed consent and continuing throughout the study and for at
least 4 months after the final dose of study drug.
- If sexually active with a person who is pregnant or breastfeeding, must consistently use 1 of 2 contraception options (as defined in Appendix D) starting at the time of informed consent and continuing throughout the study and for at least 4 months after the final dose of study drug.
- Patients who are breastfeeding, pregnant, or planning to become pregnant from time of informed consent until 2 months after final dose of study drug administration.
- Known hypersensitivity to any excipient contained in the drug formulation of PRO1184.
- Estimated life expectancy <12 weeks
- Other serious underlying medical condition that, in the opinion of the investigator, would impair the patient’s ability to receive or tolerate the planned treatment and follow-up.
- Patients with a baseline QTcF of > 480 ms.
- Dallas, TX - Mary Crowley Cancer Research - Medical City