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.
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
- Other Systemic Therapy: Previous treatment with Hh pathway antagonists is not
allowed (except for Smoothened inhibitors). There is no limit to the other prior
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
Longest of one of the following:
- Two weeks,
- 5 half-lives for investigational agents,
- 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
- 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)
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
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
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
7. Difficulty with swallowing oral medications
8. Chronic diarrhea (excess of 2-3 stools/day above normal frequency)