Treatment Duration Increment and Pharmacodynamic Study of CX-4945 in Patients With Basal Cell Carcinoma (BCC)

Inclusion Criteria

• Signed, written IRB-approved informed consent.
• Men and women age ≥ 18 years
• ECOG Performance status 0 or 1
• For patients with mBCC, histologic confirmation of distant BCC metastasis (e.g., lung, liver, lymph nodes, or bone), with metastatic disease that is RECIST measurable using CT or MRI

Phase I Expansion:

If a patient with locally advanced BCC also has a tumor that is not contiguous with cutaneous BCC, e.g., regional lymph nodes (if confirmed on biopsy as BCC and RECIST measurable), the patients should be considered as having mBCC and should be enrolled in the mBCC cohort

• For patients with locally advanced BCC, histologically confirmed disease with at least one lesion that was 10 mm or more in at least 1 dimension by color photograph that is considered to be inoperable or medical contraindication to surgery (see below), in the opinion of a Mohs dermatologic surgeon, head and neck surgeon, or plastic surgeon
• Acceptable medical contraindications to surgery include:
• BCC that has recurred in the same location after two or more surgical procedures and curative resection is deemed unlikely
• Anticipated substantial morbidity and/or deformity from surgery (e.g., removal of all or part of a facial structure, such as nose, ear, eyelid, eye; or requirement for limb amputation)
• Other conditions considered to be medically contraindicating must be discussed with the Medical Monitor before enrolling the patient.
• For all patients, smoothened inhibitor must have been previously administered for their locally advanced or metastatic BCC, unless smoothened inhibitor is inappropriate (e.g., patient has received a smoothened inhibitor but became intolerant to the therapy). For patients whose BCC has been treated with smoothened inhibitor, disease must have progressed after treatment.
• For patients with locally advanced BCC, radiotherapy must have been previously administered for their locally advanced BCC, unless radiotherapy is contraindicated or inappropriate (e.g., hypersensitivity to radiation due to genetic syndrome such as Gorlin syndrome, limitations because of location of tumor, or cumulative prior radiotherapy dose). For patients whose locally advanced BCC has been irradiated, disease must have progressed after radiation.
• Previous Therapy
• Surgery: Previous surgery is permitted provided that a minimum of 28 days (4 weeks) have elapsed between any major surgery and date of registration, and that wound healing has occurred.
• Cytotoxic Chemotherapy: There is no limit to the number of prior regimens received.
• Other Systemic Therapy: Previous treatment with Hh pathway antagonists is not allowed (except for Smoothened inhibitors). There is no limit to the other prior therapies received

Patients must have recovered (to baseline or ≤ grade 1) from all reversible toxicity related to prior chemotherapy or systemic therapy and have adequate washout as follows:

Longest of one of the following:

• Two weeks,
• 5 half-lives for investigational agents,
• For anti-cancer therapies with half-lives > 8 days, a washout period of at least 28 days will be acceptable,
• Standard cycle length of standard therapies.
• Patients with nevoid BCC syndrome (Gorlin syndrome) may enroll in this study but must meet the criteria for locally advanced or metastatic disease listed above.
• For patients with locally advanced BCC, willingness to consent to biopsy of tumor(s) at baseline and during the study, as mandated by the protocol
• Adequate hematopoietic capacity, as defined by the following:
• Hemoglobin ≥ 9.0 g/dL and not transfusion dependent
• Platelets ≥ 100,000/mm3
• Absolute neutrophil count ≥ 1500 cells/mm3
• Adequate hepatic function, as defined by the following:
• AST and ALT ≤ 2.5 times upper limit of normal (ULN) or ≤ 5 times ULN if liver metastases are present
• Total bilirubin ≤ 1.5 x ULN or within 3x the ULN for patients with Gilbert disease
• Albumin ≥ 3.0 g/dL
• Adequate renal