The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a p53 Y220C Mutation (PYNNACLE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pmv Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 May 2024 → ongoing

Decision date (initial)

2024-04-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

PMV Pharmaceuticals Inc.

External identifiers

EU CT number

2023-504251-27-00

ClinicalTrials.gov

NCT04585750

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Others, Efficacy, Safety

To evaluate the efficacy of rezatapopt per Blinded Independent Central Review (BICR) assessment.

Secondary objectives 1

1. 1. To evaluate the efficacy of rezatapopt per Investigator assessment. 2. To evaluate the safety and tolerability of rezatapopt. 3. To assess additional efficacy parameters. 4. To describe the concentrations of rezatapopt (and metabolism) when rezatapopt is administered orally. 5. To characterize the PK of rezatapopt when administered orally. 6. To evaluate the effects of rezatapopt on changes from baseline in quality of life.

Conditions and MedDRA coding

Locally Advanced or Metastatic Solid Tumors Harboring a TP53 Y220C Mutation

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices, Food And Drug Administration, Swedish Medical Products Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. Patient is at least 18 years of age.
2. 2. Patient understands the study procedures and agrees to participate by giving written, signed, and dated informed consent prior to any mandatory study-specific procedures, sampling, or analysis.
3. 3. Patient has an ECOG status of 0 or 1
4. 4. Patient has a histologically or cytologically confirmed locally advanced or metastatic solid malignancy with a TP53 Y220C mutation identified by an analytical validated assay in a certified testing laboratory.
5. 5. Patients must have received prior standard therapy appropriate for their tumor type and stage of disease and have documented radiographic progression during or after their most recent line of anticancer therapy, or in the opinion of the Investigator are ineligible for appropriate standard of care therapy. 5a. Patients with ovarian cancer must be platinum resistant defined as disease progressing within 6 months of platinum-based chemotherapy or platinum-refractory defined as disease progressing during therapy or within 4 weeks after last dose.
6. 6. Patients with CRPC must have ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor, or orchiectomy (medical or surgical castration).
7. 7. Patient has adequate organ function as defined as: • Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN) or for patients with Gilbert’s syndrome, direct bilirubin ≤ 1.5 x ULN, ALT and AST ≤ 3.0 x ULN for patients without liver metastasis and ≤ 5.0 x ULN for patients with liver metastasis; albumin > 3g/dl. • Renal: Estimated Glomerular Filtration Rate (eGFR) must be ≥ 40 mL/min. •Hematological: ANC ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL. • Serum potassium, calcium, magnesium, and phosphorus within normal limits or ≤ Grade 1. If values are low on the initial screening assessment, supplements may be given and values repeated to confirm within normal limits or ≤ Grade 1.
8. 8. Female patients of childbearing potential must have a negative urine or serum pregnancy test within 3 days prior to first dose of study drug or be of non-childbearing potential. Non-childbearing potential is defined as: • Postmenopausal, defined as no menses for 12 months without an alternative medical cause. A follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. • Surgically sterile.
9. 9. Patients who are females of childbearing potential must use a highly effective method of contraception for the course of the study or be abstinent from 14 days prior to the first dose of study drug through 3 months after the last dose of study drug .Highly effective methods of contraception include (1) oral, injected, or implanted hormonal methods of contraception that inhibit ovulation, (2) intrauterine device, (3) intrauterine hormone-releasing system, (4) bilateral tubal occlusion/ligation, (5) vasectomized partner with verified absence of sperm in ejaculate post-vasectomy. Barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception. If used, this method must be used in combination with another acceptable method listed above. Refer to Appendix 2 for contraceptive guidance. For patients with breast cancer, the following methods of contraception are not acceptable, and an alternative form of contraception should be used: • Oral, injected, or implanted hormonal methods of contraception • Intrauterine hormone-releasing systems Instead, patients with breast cancer should use one of the following highly effective methods of contraception: • Intrauterine device • Bilateral tubal occlusion/ligation • Vasectomized partner with verified absence of sperm in ejaculate post-vasectomy
10. 10.Patients who are males and have a female partner of childbearing potential must (1) use a condom, both for contraception and to protect any existing pregnancy and should also be advised of the benefit for a female partner to use a highly effective method of contraception, as described in inclusion criterion #9, or (2) agree to be abstinent from heterosexual intercourse as their preferred and usual lifestyle. These requirements should be followed starting with the first dose of study drug through 3 months after the last dose of study drug. Refer to Appendix 2 for contraceptive guidance.
11. 11. Patients must be willing to undergo a tumor biopsy during screening for NGS if an archival tumor specimen is not available and if the procedure is in line with standard of care (i.e., of low risk to patient and the tumor is of sufficient size to be biopsied).
12. 12. Patient has a life expectancy of at least 3 months as assessed by the Investigator.
13. 13. Measurable disease per RECIST v1.1 as assessed by the Investigator, with the last imaging performed within 28 days before C1D1.

Exclusion criteria 19

1. 1. Patient has received prior chemotherapy, targeted therapy, immunotherapy, or treatment with an investigational anticancer agent within 21 days or 5 half-lives (if half-life is known), whichever is shorter, before receiving their first dose of study drug.
2. 10. Patient with dysphagia that could interfere with the ability to swallow tablets.
3. 11. Patient has a history of prior organ transplant.
4. 12. Patient has any medical condition that would, in the Investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures.
5. 13. Patient has any other known, active malignancy, except for treated cervical intraepithelial neoplasia, or non-melanoma skin cancer.
6. 14. Patient has a known, active uncontrolled Hepatitis B infection (i.e., viral load above the limit of quantification), Hepatitis C infection (i.e., viral load above the limit of quantification), or human immunodeficiency virus infection (viral load > 400 copies/mL). Patients whose viral load is controlled should be on established antiretroviral therapy for at least 4 weeks prior to receiving their first dose of rezatapopt.
7. 15. Female patients that are breastfeeding or bottle feeding with their breast milk.
8. 16. Patient has any unresolved toxicities from prior anti-cancer therapy greater than Grade 1 at the time of starting rezatapopt treatment with the exception of alopecia and Grade 2 prior chemotherapy induced neuropathy.
9. 17. Patient has had major surgery within 2 weeks prior to the planned start of rezatapopt treatment.
10. 18. Patient has a known or suspected hypersensitivity to rezatapopt or any of its excipients.
11. 2. Patient has received radiotherapy within 14 days.
12. 3. Patient has a primary CNS tumor.
13. 4. Patient has history of leptomeningeal disease or spinal cord compression.
14. 5. Patient has brain metastases. Exception: Patients with brain metastases are permitted if they are neurologically stable and do not require steroids to treat associated neurological symptoms.
15. 6. Patient has had a stroke or transient ischemic attack within 6 months prior to screening.
16. 7. Patient has had one or more of the following cardiac criteria: • Unstable angina within 6 months prior to screening • Myocardial infarction within 6 months prior to screening • New York Heart Association Class II or greater congestive heart failure • QT interval corrected (QTc) using Fridericia’s formula (QTcF) > 470 msec obtained as the mean from 3 consecutive resting ECGs. Exception: A QTcF value corrected for wide QRS > 120 msec (QTcFBBB) should be used in place of QTcF for patients with non-clinically significant wide QRS > 120 msec due to a pacemaker or bundle branch block • Clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block) • Congenital long QT syndrome • Uncontrolled hypertension
17. 8. Patient treated with any of the following medications prior to receiving rezatapopt within the below time windows: • Strong CYP3A4 inducers within 14 days of first dose of rezatapopt • Strong CYP2C9 inhibitors/inducers within 14 days of first dose of rezatapopt
18. 9. Patient has a history of GI disease that may interfere with absorption of study drug (e.g., ulcerative colitis, Crohn’s disease, repeat bowel obstruction, significant nausea or frequent vomiting, severe GERD, severe diarrhea, malabsorption syndrome, or small bowel/gastric resection).
19. 19. Patient whose tumor harbors a known KRAS mutation, defined as a single nucleotide variant (SNV).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 1. Overall Response Rate (ORR) per Blinded Independent Central Review (BICR) assessment (RECIST v1.1) across all cohorts.
2. 2. ORR per BICR assessment (RECIST v1.1) in ovarian cancer cohort.

Secondary endpoints 8

1. 1. ORR across all cohorts- RECIST v1.1 as assessed by Investigator
2. 2. ORR in ovarian cancer cohort - RECIST v1.1 as assessed by Investigator
3. 3. Incidence of AEs and SAEs, and changes between baseline and post-baseline laboratory assessments, ECGs, ECOG performance status, vital signs, and physical exams. Toxicities will be graded using CTCAE v5.0 (NCI, 2017)
4. 4. TTR, DoR, DCR at 6, 12, 18, and 24 weeks, PFS across all cohorts and in ovarian cancer only - RECIST v1.1 as assessed by BICR - RECIST v1.1 as assessed by Investigator
5. 5. OS across all cohorts and in ovarian cancer only
6. 6. Rezatapopt concentrations (and concentrations of metabolites)
7. 7. Plasma PK parameters: Cmax, Tmax, AUC0-t, AUCtau, Ctrough/Ctau
8. 8. EORTC QLQ-C30

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pmv Pharmaceuticals Inc.

Sponsor organisation

Pmv Pharmaceuticals Inc.

Address

400 Alexander Park Suite 301

City

Princeton

Postcode

08540-6797

Country

United States

Scientific contact point

Organisation

PMV Pharmaceuticals Inc.

Contact name

Marc Fellous

Public contact point

Organisation

PMV Pharmaceuticals Inc.

Contact name

Clinical Study Information Center

Third parties 18

Locations

4 EU/EEA countries · 30 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 65 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications