The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE) (NCT04585750) — USA Trial Details

Condition(s) studied

Advanced Solid TumorAdvanced Malignant NeoplasmMetastatic CancerMetastatic Solid TumorLung CancerOvarian CancerEndometrial CancerProstate CancerColorectal CancerBreast CancerOther CancerLocally AdvancedHead and Neck CancerGall Bladder CancerSmall Cell Lung CancerSmall Cell Lung Cancer ( SCLC )Small Cell Lung CarcinomaNSCLCNSCLC (Non-small Cell Lung Cancer)SCLCNon-Small Cell Lung CarcinomaTriple Negative Breast CancerTNBCHER2+ Breast CancerNon-Small Cell Lung CancerER/PR Positive Breast CancerHER2- Breast CancerHER2-positive Breast CancerHER2-negative Breast CancerER/PR(+), Her2(-) Breast Cancer

Investigational drug(s) / intervention(s)

rezatapoptpembrolizumab

rezatapopt: First-in-class, oral, small molecule p53 reactivator selective for the TP53 Y220C mutation.

pembrolizumab: Participants receive pembrolizumab 200 mg by intravenous (IV) infusion over 30 minutes.

Study summary

The Phase 2 monotherapy portion of this study is currently enrolling and will evaluate the efficacy and safety of PC14586 (INN rezatapopt) in participants with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The Phase 1 portion of the study will assess the safety, tolerability and preliminary efficacy of multiple dose levels of rezatapopt as monotherapy and in Phase 1b in combination with pembrolizumab.

Eligibility

Sex

ALL

Min age

12 Years

Max age

—

Healthy volunteers

No

Inclusion Criteria: * At least 18 years of age or 12 to 17 years of age after Safety Review Committee approval. * Locally advanced or metastatic solid malignancy with a TP53 Y220C mutation * Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 * Previously treated with one or more lines of anticancer therapy and progressive disease * Adequate organ function * Measurable disease per RECIST v1.1 (Phase 2) Additional Criteria for Inclusion in Phase 1b (rezatapopt) + pembrolizumab combination) * Anti-PD-1/PD-L1 naive or must have progressed on treatment * Measurable disease Exclusion Criteria: * Anti-cancer therapy within 21 days (or 5 half-lives) of receiving the study drug * Radiotherapy within 14 days of receiving the study drug * Primary CNS tumor * History of leptomeningeal disease or spinal cord compression * Brain metastases, unless neurologically stable and do not require steroids to treat associated neurological symptoms * Stroke or transient ischemic attack within 6 months prior to screening * Heart conditions such as unstable angina within 6 months prior to screening, uncontrolled hypertension, a heart attack within 6 months prior to screening, congestive heart failure, prolongation of QT interval, or other rhythm abnormalities * Strong CYP3A4 inducers and strong CYP2C9 inhibitors/inducers within 14 days of first dose of rezatapopt * History of gastrointestinal (GI) disease that may interfere with absorption of study drug or patients unable to take oral medication * History of prior organ transplant * Known, active malignancy, except for treated cervical intraepithelial neoplasia, or non-melanoma skin cancer * Known, active uncontrolled Hepatitis B, Hepatitis C, or human immunodeficiency virus infection Additional Criteria for Exclusion from Phase 2 (rezatapopt monotherapy) * Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2) Additional Criteria for Exclusion from Phase 1b (rezatapopt) + pembrolizumab combination) * Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor and discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE) * Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention * Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy within 7 days prior to the first dose of study drug * Hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients * Active autoimmune disease that has required systemic treatment in past 2 years * History of radiation pneumonitis * History of (non-infectious) or active pneumonitis / interstitial lung disease that required steroids * Active infection requiring systemic therapy * Known history of HIV infection * Has previously received rezatapopt

Primary outcome measure(s)

Phase 1 Monotherapy (Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt — 40 months
Number of participants with treatment related adverse events
Phase 1 Monotherapy (Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) — 30 months
RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
Phase 1 Monotherapy (Dose Escalation): Establish the maximum tolerated dose (MTD) (Phase 1) — The first 28 days of treatment (Cycle 1) per patient
Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with rezatapopt
Phase 1b Combination Therapy (Part 1: Dose Escalation): Determine the number and type of adverse events to characterize the safety of rezatapopt when administered in combination with pembrolizumab — 18 months for treatment arm
Number of participants with treatment related adverse events
Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the maximum tolerated dose (MTD) of rezatapopt when administered in combination with pembrolizumab — The first 28 days of combination treatment arm (starting on Day -7) per patient
Incidence of dose limiting toxicities (DLTs) during the first 28 days of treatment with rezatapopt
Phase 1b Combination Therapy (Part 1: Dose Escalation): Establish the Recommended Phase 2 Dose (RP2D) of rezatapopt when administered in combination with pembrolizumab — 18 months
RP2D will be determined using available safety and pharmacokinetics and pharmacodynamics data
Phase 1b Combination Therapy (Part 2: Dose Expansion): Determine the number and type of adverse events to characterize the safety of rezatapopt when administered in combination with pembrolizumab — 12 months for treatment arm
Number of participants with treatment related adverse events
Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt — 34 months
Overall response rate in accordance with Response Evaluation Criteria (RECIST) v.1.1 as assessed by independent review across all cohorts
Phase 2 Monotherapy (Dose Expansion): Response rate assessment to evaluate the clinical activity / efficacy of rezatapopt in ovarian cancer patients — 34 months
Overall response rate in accordance with Response Evaluation Criteria (RECIST) v.1.1 as assessed by independent review in the ovarian cancer cohort

Trial sites (77)

Facility	City	Region	Status
University of California Irvine Chao Family Comprehensive Cancer Center	Irvine	California	Withdrawn
University of San Diego Moores Cancer Center	La Jolla	California	Recruiting
UCLA Jonsson Comprehensive Cancer Center	Los Angeles	California	Recruiting
USC Norris Comprehensive Cancer Center	Los Angeles	California	Recruiting
Rocky Mountain Cancer Center	Denver	Colorado	Recruiting
Yale Cancer Center	New Haven	Connecticut	Recruiting
Medical Oncology Hematology Consultants	Newark	Delaware	Recruiting
University of Miami - Sylvester Comprehensive Cancer Center	Miami	Florida	Recruiting
Advent Health	Orlando	Florida	Recruiting
Florida Cancer Specialists South	Port Charlotte	Florida	Recruiting
Massachusetts General Hospital	Boston	Massachusetts	Recruiting
Dana Farber Cancer Institute	Boston	Massachusetts	Recruiting
Karmanos Cancer Institute	Detroit	Michigan	Recruiting
University of Nebraska Medical Center Buffet Cancer Center	Omaha	Nebraska	Not Yet Recruiting
Columbia University Medical Center	New York	New York	Not Yet Recruiting
Memorial Sloan Kettering	New York	New York	Recruiting
Duke University	Durham	North Carolina	Recruiting
The Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	Recruiting
University of Oklahoma	Oklahoma City	Oklahoma	Recruiting
Oregon Health & Science University (OHSU)	Portland	Oregon	Recruiting
Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	Recruiting
University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	Recruiting
WellSpan York Cancer Center	York	Pennsylvania	Recruiting
Medical University of South Carolina	Charleston	South Carolina	Terminated
Sarah Cannon Research Institute	Nashville	Tennessee	Recruiting
New Experimental Therapeutics - NEXT Oncology	Austin	Texas	Recruiting
Texas Oncology	Bedford	Texas	Recruiting
UT Southwest Simmons Cancer Center	Dallas	Texas	Recruiting
The University of Texas MD Anderson Cancer Center	Houston	Texas	Recruiting
New Experimental Therapeutics of San Antonio - NEXT Oncology	San Antonio	Texas	Recruiting
Virginia Cancer Specialists	Fairfax	Virginia	Recruiting
University of Washington, Fred Hutchinson Cancer Center	Seattle	Washington	Recruiting
University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	Recruiting
Chris O'Brien Lifehouse Hospital	Camperdown	New South Wales	Recruiting
Mater Cancer Care Centre	South Brisbane	Queensland	Recruiting
Flinders Medical Center	Bedford Park	South Australia	Recruiting
Monash Medical Centre	Clayton	Victoria	Recruiting
Linear Clinical Research	Nedlands	Western Australia	Recruiting
ICANS - Institut de cancérologie Strasbourg Europe	Strasbourg	Bas-Rhin	Recruiting
Institut Bergonie	Bordeaux	Gironde	Recruiting

+ 37 more sites — see the full list on the official registry below.