IRB Study Number 25-996
Status Recruiting
Phases Phase 1, Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
DOSE ESCALATION (PART 1)
Primary Objective(s): To determine the safety, tolerability, and MTD (or MAD) of CP-383 in advanced solid tumors
Secondary Objective(s):
• To characterize the PK parameters of CP-383 and assess dosing regimens
• To evaluate the safety and tolerability of CP-383 in advanced solid tumors
Exploratory Objective(s):
• To evaluate preliminary efficacy of CP-383
• To evaluate tumor genomic alterations and response to CP-383
• To characterize the PD effects of CP-383
• To explore the metabolite profile of CP-383 in plasma
DOSE EXPANSION (PART 2)
Primary Objective(s): To further evaluate efficacy of CP-383 at the RP2D in selected tumor types
Secondary Objective(s):
• To further characterize the safety and tolerability of CP-383 in selected tumor types at the RP2D
• To further evaluate efficacy of CP-383 at the RP2D in selected tumor types
Exploratory Objective(s):
• To further characterize the PK parameters of CP-383 in selected tumor types at the RP2D
• To further explore the metabolite profile of CP-383 in plasma
• To further characterize the pharmacodynamic (PD) effects of CP-383
• To evaluate tumor genomic alterations and response to CP-383
• To evaluate ctDNA and response to CP-383
Inclusion Criteria
To be included in this study, each individual must satisfy all the following criteria:
- Male or female ≥18 years of age at time of informed consent.
- ECOG Performance Status of 0-1
- Measurable or non-measurable disease for Dose Escalation (non-backfill) and measurable disease for Dose Escalation Backfill and Dose Expansion as defined by RECIST v1.1
- Life expectancy ≥12 weeks according to investigator’s judgement
- Patients must have refused, or not be eligible for further standard therapies expected to provide clinical benefit in their specific disease
- Availability of suitable archival tumor tissue for retrospective gene mutation analysis at a Sponsor designated laboratory
a. For patients without archival tissue, a tumor biopsy must be obtained and must be investigator assessed as low risk. Exceptions for patient safety/unacceptable risk may be considered with Sponsor approval. - Disease diagnosis and requirements:
a. All patients must have histological documentation of locally advanced, recurrent, or metastatic incurable disease that is refractory or has progressed.
b. Dose Escalation Part 1 (escalation and backfill): Solid tumor (excluding primary CNS tumors) malignancy that is refractory to or has progressed after at least one line of therapy; or for whom standard therapy has proven to be ineffective or intolerable or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized standard of care
c. Dose Escalation Part 1 (backfill only): Diagnosis of one of the following cancers:
i. CRC
ii. SCLC
iii. HNSCC
iv. NSCLC
v. PC
vi. Bladder
Note: Selected Patients (in each of the tumor specific backfill tumor types): Confirmation of biomarker eligibility: Valid results from testing of or tumor tissue documenting the presence of LOF mutations in either CREBBP, EP300, and/or FAT1 genes
• Prior local testing of tumor tissue must be performed using a Sponsor-approved NGS assay performed at a CLIA or equivalently certified laboratory
With Sponsor prior approval: Patients without available test results for tumor mutation status must submit an archival or fresh tumor biopsy sample (refer to biopsy restrictions above) to determine whether an eligible mutation is present documenting the LOF mutations in either CREBBP, EP300, and/or FAT1 genes. Note this sample can also be used for submission to the Sponsor for required retrospective testing.
vii. Other Solid Tumors (excluding primary CNS tumors, and tumor specific backfill tumor types) with evidence of LOF mutations in either CREBBP, EP300, and/or FAT1 genes.
Confirmation of biomarker eligibility: Valid prior results from testing of tumor tissue documenting the presence of LOF mutations in either CREBBP, EP300, and/or FAT1 genes
• Prior local testing of tumor tissue must be performed using a Sponsor-approved NGS assay performed at a CLIA or equivalently certified laboratory
d. Dose Expansion (Part 2): Diagnosis of one of the following:
i. CRC: Adenocarcinoma of the colon or rectum with disease progression or intolerance to at least 1 prior line of therapy, but no more than 5 lines of therapy
ii. SCLC: Small cell lung cancer with disease progression or intolerance to at least 1 prior line of therapy, but no more than 3 lines of therapy
iii. HNSCC: Head and neck squamous cell carcinoma with disease progression after at least 1 prior line of therapy, but no more than 5 lines of therapy
Note: Selected patients in each of the above disease specific cohorts: Confirmation of biomarker eligibility: Valid results from prior testing of, or Sponsor approved new tumor tissue testing documenting the presence of loss of function (LOF) mutations in either CREBBP, EP300, and/or FAT1 genes – as described for Dose Escalation Backfill
iv. Other Solid Tumors (excluding primary CNS tumors): solid tumors other than those in disease specific cohorts with evidence of LOF mutations in either CREBBP, EP300 and/or FAT1 genes with disease progression or intolerance to at least 1 prior line of therapy, but no more than 5 lines of therapy
Confirmation of biomarker eligibility: Valid results from prior testing of, or Sponsor approved new tumor tissue testing documenting the presence of LOF mutations in either CREBBP, EP300, and/or FAT1 genes – as described for Dose Escalation tumor specific backfill cohort requirements - Adequate hematologic and organ function within 14 days prior to initiation of the study treatment, defined by the following:
a. Absolute neutrophil count (ANC) ≥1.5 x 109/L
b. Platelet count ≥100 x 109/L
c. Hemoglobin ≥9 g/dL
d. Total bilirubin ≤1.5 x ULN or ≤3.0 x ULN in case of Gilbert’s syndrome
e. Serum albumin ≥3.0 g/dL
f. AST & ALT ≤3.0 x ULN, but ≤5.0 x ULN in the presence of liver metastases
g. Calculated creatinine clearance ≥40 mL/min (Cockcroft-Gault) - For women of childbearing potential, agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, as defined below:
a. Women must remain abstinent or use contraceptive methods with a failure rate of <1% per year during the treatment period and for 6 months after the final dose of CP-383. Women must refrain from donating eggs during this same period.
b. A woman is considered of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations
c. Examples of contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
d. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not adequate methods of contraception - For men who are not surgically sterile, agreement to remain abstinent or use contraception, and agreement to refrain from donating sperm, as defined below:
a. With a female partner of childbearing potential who is not pregnant, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for 4 months after the final dose of CP-383. Men must also refrain from donating sperm during this same period
b. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not adequate methods of contraception - Understands the procedures and requirements of the study and provides written informed consent and authorization for protected health information disclosure
- Willing and able to comply with the requirements of the study protocol
Exclusion Criteria
If an individual meets any of the following criteria, he or she is ineligible for this study:
- Inability or unwillingness to swallow pills
- Inability to tolerate oral intake that includes two full meals per day (or equivalent caloric intake in frequent small meals)
- Patients on supplemental peripheral nutrition
- Malabsorption syndrome or other condition that would interfere with enteral absorption
- Known history of HIV, unless on effective anti-retroviral therapy with an undetectable viral load within 6 months of Day 1 of Cycle I
- Known history of viral hepatitis B unless HBV viral load is below the limit of quantification and off viral suppressive therapy
- Known history of hepatitis C unless antiviral treatment with curative intent completed and HCV viral load is below the limit of quantification
- Patients with known active central nervous system (CNS) primary or metastatic disease, progressing or requiring anticonvulsants or corticosteroids for symptomatic control. Patients with a history of treated CNS metastases are eligible, provided they meet all the following criteria
a. Measurable or evaluable disease outside of the CNS, no CNS lesion greater than 3 cm
b. No history of intracranial hemorrhage or spinal cord hemorrhage, or herniation
c. No ongoing requirement for corticosteroids as therapy for CNS metastases, with corticosteroids discontinued for ≥ 2 weeks prior to enrollment and no ongoing symptoms attributed to CNS metastases
d. No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to Day 1 of Cycle 1
e. No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study - Infection requiring IV antibiotics within 7 days prior to Day 1 of Cycle 1
- Clinically significant history of liver disease, including due to viral or other hepatitis, current alcohol abuse, or cirrhosis
- Patients with chronic diarrhea, short bowel syndrome or significant upper gastrointestinal surgery including gastric resection, a history of inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis) or any active bowel inflammation (including diverticulitis)
- History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer or other malignancy that is in remission or stable and for which patients have not been on active anti-cancer therapy for ≥2 years
- History of, or active clinically significant cardiovascular dysfunction, including the following:
a. History of stroke or transient ischemic attack within 6 months of Day 1 of Cycle 1
b. NYHA Class III or IV cardiac disease or congestive heart failure requiring medication
c. Uncontrolled arrhythmias, history of or active ventricular arrhythmia requiring medication
d. Coronary heart disease that is symptomatic or unstable angina
e. Congenital long QT syndrome or QT interval corrected through use of Fridericia's formula (QTcF) > 470 ms demonstrated by at least two ECGs > 30 minutes apart, or family history of sudden unexplained death or long QT syndrome
f. Uncontrolled hypertension: SBP >160, or DBP >100 on optimal therapy - Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the patients at high risk for treatment complications
- Significant traumatic injury or major surgical procedure within 4 weeks prior to Day 1 of Cycle 1
- Pregnant or lactating. If HCG is elevated, eligible if ultrasound confirms absence of a pregnancy
- Bowel obstruction requiring medical management less than 4 weeks prior to screening
- Uncontrolled pleural effusion, pericardial effusion, or recurrent ascites requiring recurrent drainage more frequently than every 4 weeks or within 14 days of screening
- Patients with known hypersensitivity to excipients in Phosal 53 MCT
- Prior/Concomitant Therapy
a. Exposure to any other anti-cancer therapy within 14 days, or five half-lives prior to Day 1 of Cycle 1, (if known) whichever is shorter
b. Received transfusion (platelets or RBCs) or growth factor support ≤2 weeks prior to Screening hematology testing
c. Currently on systemic corticosteroid treatment for cancer or non-cancer indications at a daily dose equivalent to >10 mg of prednisone
d. Currently on systemic antibiotic, antifungal or anti-viral therapy (with exception of anti-retroviral therapy use for HIV), unless for UTI or prophylaxis
e. Currently receiving treatment with medications that are strong/moderate inhibitors or inducers of both CYP3A and CYP2C8 and cannot be discontinued 1 week (inhibitors) or 2 weeks (inducers) prior to the start of CP-383 treatment and for the duration of the study
f. Currently receiving treatment with proton pump inhibitors and cannot be discontinued 1 week (or 5 half-lives whichever is longer) prior to the start of CP-383 treatment and for the duration of the study
g. Currently receiving treatment with sensitive substrates of CYP2B6, CYP2C8, CYP2C9, or CYP3A with a narrow therapeutic index and cannot be discontinued 1 week prior to the start of CP-383 treatment and for the duration of the study
