Topical Remetinostat in Treating Patient With Cutaneous Basal Cell Cancer

PRIMARY OBJECTIVES:

I. Overall response rate of basal cell carcinoma (BCC) in subjects at 6 weeks.

SECONDARY OBJECTIVES:

I. Suppression of GLI1 (glioma-associated oncogene) expression in treated BCCs as compared with baseline.

II. Safety assessment of Remetinostat after 6 weeks of topical treatment.

OUTLINE:

Tumors receive Remetinostat topically three times per day (TID) for 6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for at least 4 weeks.

• Remetinostat (Drug), also known as suberohydroxamic acid phenyl ester (SHAPE); SHAPE Gel; SHP 141; and 4 [[8 (hydroxyamino) 1,8 dioxooctyl]oxy] benzoic acid methyl ester: Applied topically under bandage occlusion

Primary outcomes

• Overall Response Rate [At 6 weeks]: Overall response is defined as achieving either a complete response (CR) or a partial response (PR). Response is based on the Response Evaluation Criteria in Solid Tumors (RECIST), as follows. * CR = tumor lesion becomes undetectable * PR = ≥30% decrease in total tumor diameter * Overall response (OR) = CR+PR * Stable Disease (SD) = decrease in total tumor diameter is >0% and <30% * Progressive Disease (PD) = increase in total tumor diameter Exact binomial 90% confidence intervals (90%) will be computed for OR. The data are reported accord to the per protocol analysis, ie, including lesions for subjects who were <70% compliant with drug treatment. For subjects who were compliant but dropped out, data from their last study visit will be used if they contribute a biopsy. The analysis population will include the participants who have provided pre-treatment and post-treatment biopsies. The outcome is reported as the percent of tumor lesions that achieve OR, with 90% CI.

Secondary outcomes

• Number of Participants With a Decrease in Expression of the Hedgehog Biomarker Gene GLI1 [6 weeks]: The effect of topical remetinostat gel 1% on decreasing expression of Hedgehog biomarker gene GLI1 was determined using the RNeasy Fibrous Tissue Mini Kit (Qiagen, Valencia, CA), a polymerase chain reaction (PCR) test kit. The levels observed at baseline and after 6 weeks treatment were obtained. The outcome is reported as the number of subjects for whom a decrease in expression of the Hedgehog biomarker gene GLI1 was observed, a number without dispersion.
• Adverse Events Contributing to Treatment Discontinuation or Interruption [6 weeks]: Adverse events (AEs) contributing to treatment discontinuation or interruption are reported as the number of such events, a number without dispersion.
• Participants Who Discontinued Treatment or Had Treatment Interruption [6 weeks]: The number of participants who discontinued treatment or experienced treatment interruption within the first 6 weeks of treatment are reported as the number of such participants, a number without dispersion.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Must have at least one BCC lesion > 1 cm (BCC > 5 mm) in non-cosmetically sensitive site(s)
* Must be willing to apply the topical remetinostat 3 times daily for 6 weeks
* For women of child bearing potential, a negative urine pregnancy test
* Women of child bearing potential are expected to use an effective method of birth control while participating in the study and for 1 month after applying the last dose
* For male subjects with female partners of childbearing potential, agreement to use adequate contraception while participating in the study and for 1 month after applying the last dose
* Has signed and dated the current Institutional Review Board (IRB) approved informed consent document

Exclusion Criteria:

* Taking any medication known to interact with histone deacetylase (HDAC) inhibitors, such as valproate or anticoagulants
* Taking any medication known to affect hedgehog (HH) signaling pathway such as itraconazole
* Within the past 6 months, has used topical or systemic therapies that might interfere with the evaluation of the study medication during the study; specifically, these include the topical use to the study tumors of:

  * Glucocorticoids
  * Retinoids either systemically or topically (eg, etretinate, isotretinoin, tazarotene, tretinoin, adapalene)
  * Alpha hydroxy acids (eg, glycolic acid, lactic acid) to > 5% of the skin
  * 5 fluorouracil or imiquimod and/or
  * Itraconazole
* Has received treatment with systemic chemotherapy or agents known to be inhibitors of HH signaling, within 60 days to starting study medication
* Currently receiving systemic medications that could affect BCC tumors (eg, oral retinoids) or might interact with remetinostat
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, recurrent seizure history or psychiatric illness/social situations that would limit compliance with study requirements
* Moderate to severe immunosuppression due to disease or medication
* Known or previous hypersensitivity to histone deacetylase inhibitor (HDACi)
* History of congestive heart failure; cardiac arrhythmias; or other findings of ventricular dysfunction
* History of current evidence of malabsorption or liver disease
* Pregnancy or breast feeding

Participant flow

Outcome results

• Overall Response Rate (Primary), Number, percentage of tumor lesions: Treatment (Remetinostat) 69.7 (54.0 to 82.5)
• Number of Participants With a Decrease in Expression of the Hedgehog Biomarker Gene GLI1 (Secondary), Count of participants, Participants: Treatment (Remetinostat) 5
• Adverse Events Contributing to Treatment Discontinuation or Interruption (Secondary), Number, adverse events: Treatment (Remetinostat) 9
• Participants Who Discontinued Treatment or Had Treatment Interruption (Secondary), Count of participants, Participants: Treatment (Remetinostat) 5

Adverse events

Time frame: 12 weeks

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2020-10-02)
• Informed Consent Form (PDF, 2020-04-15)

• Kavita Sarin, Principal investigator, Stanford University