rezatapopt (PC14586)

P1, N=28, Completed, PMV Pharmaceuticals, Inc | Active, not recruiting --> Completed | Trial completion date: Jun 2024 --> Feb 2024

P1, N=12, Completed, PMV Pharmaceuticals, Inc | Recruiting --> Completed

P1, N=25, Not yet recruiting, M.D. Anderson Cancer Center

"Foundation Medicine, Inc. and PMV Pharmaceuticals, Inc...announced a partnership to develop Foundation Medicine’s tissue-based comprehensive genomic profiling test, FoundationOneCDx, as a companion diagnostic for PMV Pharma’s rezatapopt, a first-in-class, investigational therapy for patients with locally advanced or metastatic solid tumors that have a TP53 Y220C mutation."

Mechanism-based combinations with XPO-1, MDM2, and Bcl-2 inhibitors induce massive apoptosis. PC14586 is presently in early clinical trials.

A novel Y220C-targeted small molecule (PC14586) has shown preliminary efficacy and safety in patients with solid tumors (Dumbrava, E., ASCO 2022)... TP53 Y220C mutations are present in malignant blood disorders and are particularly more common in myelodysplastic syndromes and acute myeloid leukemia, with associated poor outcomes. Novel targeted therapies for this TP53 variant (Y220C) would be of interest for this patient population.

No abstract available

P1/2, N=181, Recruiting, PMV Pharmaceuticals, Inc | Trial completion date: Dec 2025 --> Jul 2026 | Trial primary completion date: Nov 2024 --> Mar 2026

For example, OncoKB included 2 new tumor-agnostic FDA drug approvals, dabrafenib + trametinib and selpercatinib for BRAF V600E and RET fusion-positive solid tumors respectively (Level 1), capturing 5 tumor-agnostic FDA drug approvals to date. OncoKB promoted ERBB2 oncogenic mutations and FGFR1 fusions to Level 1 following their inclusion as patient eligibility criteria in FDA drug labels for trastuzumab deruxtecan (NSCLC) and pemigatinib (myeloid/lymphoid neoplasms) respectively...Lastly, previously considered undruggable targets, TP53 Y220C and KRAS G12D, were included in OncoKB based on compelling evidence demonstrating response to allele-targeting drugs, PC14586 and RMC-6263, respectively...Current OncoKB efforts are focused on prioritized high-volume cancer gene curation for annotation of whole exome/genome data, annotation of germline alterations and development of a clinical trials matching system. *FDA recognition of OncoKB is partial and limited to the information clearly marked on www.oncokb.org.

Recently, a Phase 1 clinical trial studying the novel Y220C-targeted small molecule PC14586, has shown preliminary safety and efficacy in patients with heavily treated solid tumors...Conclusion s : TP53 Y220C mutation is present in hematologic diseases, primarily in myeloid neoplasms (MDS and AML) and with higher frequency in therapy-related disease. Targeted therapies for this specific TP53 mutation would be of interest in this difficult to treat patient population.

Several such reactivating drugs are currently undergoing evaluation in clinical trials, including eprenetapopt (APR-246), COTI-2, arsenic trioxide and PC14586. With all of these ongoing trials, we should soon know if targeting mutant p53 can be used for cancer treatment. If any of these trials show clinical efficacy, it may be a transformative development for the treatment of patients with cancer since mutant p53 is so prevalent in this disease.

Enrollment to a Phase 1 study is feasible in a TP53 mutation selective population. PC14586 is safe and tolerated up to 3000 mg daily. Preliminary efficacy was achieved in heavily pretreated pts.

Small molecules that reactivate Y220C mutant p53 activity to be like wild type have been developed at PMV Pharmaceuticals and the lead compound PC14586 is in Phase I clinical development...Further investigation into the role of Y220C p53 reactivation in immune modulation showed decreased cytokines and chemokines involved in inflammation (i.e. CXCL10, Ccl2) and an increase in a Tumor Inflammation Signature (nanoString) in a dose and time dependent manner. Taken together, these data suggest a role for p53 signaling in encouraging an immunologically hot tumor microenvironment and provide support for testing small molecule reactivators of mutant p53 in combination with immune checkpoint inhibitors.

PC14586 is well tolerated by pre-clinical species and possesses a favorable development profile. The safety and efficacy of PC14586 is currently being evaluated in a seamless Phase I/II clinical study that is a biomarker driven, solid tumor agnostic trial with patients whose tumor bears the Y220C TP53 mutation (NCT study identifier NCT04585750).