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

A Phase I, Multi-Center, Open-Label, Treatment Duration Increment, Expansion, Safety, and Pharmacodynamic Study of CX-4945 Administered Orally Twice Daily to Patients With Advanced Basal Cell Carcinoma

This study is to determine the recommended phase II dose (RP2D) and schedule of CX-4945 when administered orally twice daily for 28 consecutive days, in a 4-week (28 days) cycle, in patients with locally advanced or metastatic basal cell carcinoma (BCC). The safety and tolerability of CX-4945, preliminary evidence of antitumor effect, and the effect of CX-4945 treatment on the Hh signaling pathway will also be evaluated in this study.

Basal cell carcinomas require the hedgehog (Hh) pathway for growth. Hh binding relieves the inhibitory effect of PTCH1 on Smoothened (SMO). Signal transduction by SMO then leads to the activation and nuclear localization of GLI1 transcription factors and induction of Hh target genes, many of which are involved in proliferation, survival, and angiogenesis. Hedgehog pathway inhibitors, such as vismodegib6 and sonidegib phosphate, target the G-protein-coupled receptor Smoothened (SMO) and are recommended as first-line treatment for advanced BCC or mBCC by the National Comprehensive Cancer Network. CK2 affects the terminal-most Hh signaling components. Given the roles of CK2 on the terminal step of the hedgehog signaling pathway, CK2 inhibition is unlikely to be overcome by downstream mutations within this pathway. These data thus suggest an immediately practical application of CX-4945 in Hh-driven tumors and possibly tumors resistant to SMO inhibitors.

Inclusion Criteria:

1. Signed, written IRB-approved informed consent.

2. Men and women age ≥ 18 years

3. ECOG Performance status 0 or 1

4. 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

5. 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

6. Acceptable medical contraindications to surgery include:

   1. BCC that has recurred in the same location after two or more surgical procedures and curative resection is deemed unlikely
   2. 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)
   3. Other conditions considered to be medically contraindicating must be discussed with the Medical Monitor before enrolling the patient.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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

12. 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

13. 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

14. Adequate renal function, as defined by the following:

    • Renal: calculated creatinine clearance >45 mL/min for patients with abnormal, increased, creatinine levels (Cockcroft-Gault formula).

15. Women/men of childbearing potential must have agreed to use two effective contraceptive methods while on study and for 6 months after the last dose of CX-4945 (see Appendix D for definition of women of childbearing potential and acceptable and unacceptable methods of contraception)

Exclusion Criteria:

1. Tumor histology consistent with basosquamous carcinoma (basal cell carcinoma with squamous differentiation or metatypical carcinoma).

2. Pregnant or nursing women. NOTE: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation. Should a man father a child, or a woman become pregnant or suspect she is pregnant while participating in this study, he or she should inform the treating physician immediately.

3. Concurrent non-protocol-specified anti-tumor therapy (e.g., chemotherapy, other targeted therapy, radiation therapy, or photodynamic therapy)

   • For patients with multiple cutaneous BCCs at baseline that are not designated by the investigator as target lesions, treatment of these non-target BCCs with surgery may be permitted but must be discussed with the Medical Monitor prior to any surgical procedure.
   • For patients with locally advanced BCC whose target lesion(s) is/are inoperable at baseline but is/are later deemed potentially operable because of tumor response to CX-4945, surgery with curative intent may be permitted but must be discussed with the Medical Monitor prior to any surgical procedure.

4. History of other malignancies within 3 years of Day 1, except for tumors with a negligible risk for metastasis or death, such as adequately treated squamous-cell carcinoma of the skin, ductal carcinoma in situ of the breast, or carcinoma in situ of the cervix

5. Active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol.

6. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or renders the patient at high risk from treatment complications

7. Difficulty with swallowing oral medications

8. Chronic diarrhea (excess of 2-3 stools/day above normal frequency)