Difficulty with patient recruitment

This research is studying the preventative use of topical 0.1% tazarotene gel daily in addition to best practice standards to reduce the development of hand-foot skin reaction (HFSR).

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has not approved tazarotene for specifically for hand-foot skin reaction but it has been approved for other uses.

In this research study, the investigators are:

-aiming to determine if the use of tazarotene gel daily, in addition to best practice standards:

• reduces the development of HFSR.
• decreases modification of regorafenib dose due to HFSR
• improves health-related quality of life associated with HFSR
• decreases stress associated with HFSR

Inclusion Criteria:

• Participants must have histologically or cytologically confirmed solid tumors with a plan to initiate regorafenib, or having started regorafenib in the last 48 hours, via dose escalation protocol describe in the ReDOS study in CRC. The ReDOS study recommends this dose escalation of regorafenib:80mg daily x 1 week, 120mg daily x 1 week, 160mg daily times one week, off week, then 160mg daily goal, or maximum tolerated dose thereafter. This is not a separate study; this is the current standard of care for regorafenib dosing. In addition, to compare across the cohorts, patients must be ambulatory with full use of all 4 distal extremities.
• Age ≥ 18
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• Participants must have sufficient organ and marrow function in the opinion of the treating investigator. This can be based on lab reports from an outside facility.
• Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation Tazarotene is known to be teratogenic, although the dose required with topical application to affect the developing human fetus is unknown. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of administration.
• Women of child-bearing potential (WOCBP) must have a negative serum pregnancy test.
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Regorafenib use in combination with another TKI (unless regorafenib was started in the last 48 hours)
• Pregnancy or non-compliance with contraception (4 weeks before, during and for at least 3 ovulatory cycles after treatment cessation). Pregnant women are excluded from this study because tazarotene is category X with the potential for teratogenic or abortifacient effects.
• Nursing or lactating: Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with tazarotene, breastfeeding should be discontinued if the mother is treated.
• A history of hypervitaminosis A
• Other systemic retinoids needed for another condition (ie. Isotretinoin for inflammatory acne, acitretin for psoriasis, bexarotene for CTCL).
• Need for treatment dose systemic steroids or systemic immunosuppressive agents (i.e., for autoimmune disease or cerebral edema) at the time of enrolment
• Psoriasis or other autoimmune disease requiring skin directed or systemic therapy known to impact keratinocyte proliferation (UV therapy to the hands or feet, TNF inhibitors, etc).
• Active skin disease of the hands or feet with redness, scaling or blisters prior to enrolment
• Participants who have had any systemic chemotherapy or immunotherapy within 4 weeks prior to entering the study AND who have not recovered from adverse events on the hands and feet due to the agents administered.
• Participants who are receiving any other investigational agents to treat HFSR.
• Uncontrolled intercurrent illness including, but not limited to, uncontrolled lower extremity edema, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research

Data can be shared no earlier than 1 year following the date of publication

BCH - Contact the Technology & Innovation Development Office at www.childrensinnovations.org or email TIDO@childrens.harvard.edu BIDMC - Contact the Beth Israel Deaconess Medical Center Technology Ventures Office at tvo@bidmc.harvard.edu BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu MGH - Contact the Partners Innovations team at http://www.partners.org/innovation

24 weeks

Of the eight participants enrolled, six reported one or more adverse events (Placebo:2, Tazarotene:4), and two reported no adverse events. All events were classified as either "unrelated" or "unlikely related" to study therapy. In the table below, each participant is classified according to the worst grade reported for each adverse event type. All events were grade 1 or 2.

This study was terminated prematurely on 7/14/2022 as there had been significant difficulty with patient recruitment.

This report includes data for eight (8) randomized participants. The first enrolled on December 30, 2019, and the last on July 28, 2020.