Alpelisib in Combination With Carboplatin in Patients With Solid Tumors and HPV-Positive Squamous Cell Carcinoma

NCT05472220 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 219515NCI-2022-03888
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase I/II trial tests the safety, side effects, and best dose of alpelisib and whether alpelisib and carboplatin work to shrink tumors in patients with solid tumors or human papillomavirus (HPV) positive squamous cell carcinoma that has spread to nearby tissue or lymph nodes (locally advanced) or has spread to other places in the body (metastatic). Alpelisib belongs to a group of medicines called phosphatidylinositol 3-kinase (PI3K) inhibitors. This means alpelisib blocks the activity of the PI3K protein. The PI3K pathway is well known to be involved in tumor cell multiplication and survival. Blocking PI3K may reduce the ability of certain cancers to grow. Carboplatin is an anticancer drug or chemotherapy drug that binds to DNA causing damage that prevents the DNA from replicating, which prevents the cells itself from reproducing. Giving alpelisib and carboplatin may help control the disease in patients with solid tumors and HPV positive squamous cell carcinoma.

Conditions

Solid Tumors, Adult; PIK3CA Mutation-Related Tumors; PIK3CA Mutation; Human Papillomavirus-Related Carcinoma; HPV-Related Squamous Cell Carcinoma; Human Papillomavirus-Related Squamous Cell Carcinoma; Locally Advanced Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm

Outcome Measures

Primary Outcomes (5)

• Maximum Tolerated Dose (MTD) (Phase 1)

  During dose escalation, two dose levels of carboplatin will be evaluated in combination with escalating doses of alpelisib in parallel. The MTD is defined as the highest combination drug dosage not causing dose-limiting toxicities (DLT) in 33% or more of the treated patients in the first 21-day cycle of treatment.

  Up to 1 cycle (1 cycle is equal to 21 days)

• Recommended Phase 2 Dose (Phase 1)

  The recommended phase 2 dose will be determined during interim analysis on toxicities reported in Phase 1, and implemented during enrollment of the phase 2 cohort.

  Up to 1 cycle (1 cycle is equal to 21 days)

• Percentage of participant with reported DLT (Phase 1)

  Toxicity will be assessed using the NCI CTCAE, version 5.0 unless otherwise specified. A DLT is defined as an AE or abnormal laboratory value assessed as at least possibly related to the study medication, which occurs \<= 21 days following the first dose of alpelisib in combination with carboplatin (Cycle 1).

  Up to 1 cycle (1 cycle is equal to 21 days)

• Percentage of participants with treatment-related adverse events

  Percentage of participants with Grade 3 and higher adverse events classified using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be reported.

  Up to 3 years

• Overall Response Rate Phase (Phase 2)

  Overall response rate (ORR) will be reported for the Phase 2 cohort and defined as the number of patients with complete response (CR) or partial response (PR) using RECIST version 1.1 criteria over the total number of patients enrolled in this study. The proportion and corresponding two-sided 90% confidence interval will be reported.

  Up to 3 years

Secondary Outcomes (2)

• Median progression-free survival (Phase 2)

  Up to 3 years

• Proportion of participants with abnormal glucose values over time

  Up to 3 years

Study Arms (2)

Phase 1: Dose Escalation

EXPERIMENTAL

Patients with advanced solid tumors will be adminsitered Alpelisib and Carboplatin in 21 day cycles until unacceptable toxicity, disease progression or death. At baseline, patients will undergo cross-sectional imaging of the abdomen with HP13C. Participants will wear a glucose monitor for the first two treatment cycles.

Drug: Alpelisib; Drug: Carboplatin; Drug: Hyperpolarized Carbon-13 (13C) Pyruvate; Device: Continuous Glucose Monitor (CGM)

Phase 2: Dose Expansion

EXPERIMENTAL

Patients with HPV+ squamous cell carcinoma will be administered the recommended phase 2 dose of Alpelisib and Carboplatin in 21 day cycles until unacceptable toxicity, disease progression or death. At baseline, patients will undergo cross-sectional imaging of the abdomen with HP13C. Participants will wear a glucose monitor for the first two treatment cycles

Drug: Alpelisib; Drug: Carboplatin; Drug: Hyperpolarized Carbon-13 (13C) Pyruvate; Device: Continuous Glucose Monitor (CGM)

Interventions

Alpelisib DRUG

Given orally

Also known as: BYL719, Phosphoinositide 3-kinase Inhibitor BYL719

Phase 1: Dose Escalation; Phase 2: Dose Expansion

Carboplatin DRUG

Given IV during imaging

Also known as: Paraplatin

Phase 1: Dose Escalation; Phase 2: Dose Expansion

Hyperpolarized Carbon-13 (13C) Pyruvate DRUG

Given IV

Also known as: Hyperpolarized [1-13C]pyruvate

Phase 1: Dose Escalation; Phase 2: Dose Expansion

Continuous Glucose Monitor (CGM) DEVICE

Self-applied devices that sit partially beneath the skin

Phase 1: Dose Escalation; Phase 2: Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to understand and voluntarily sign the informed consent form, and able to comply with the study visit schedule and other protocol requirements. Written informed consent obtained prior to any screening procedures.
• Age \>= 18 years.
• Dose escalation-
• Any locally advanced or metastatic solid tumor malignancy with no curative treatment options available.
• Dose expansion- a. HPV-associated locally advanced or metastatic platinum-resistant squamous cell carcinoma with no treatments available known to confer clinical benefit. If patients enrolled to the dose expansion have alternative therapies available known to confer clinical benefit, patients will be informed of these therapies in the informed consent.
• b. HPV positivity defined by positive p16 immunohistochemistry, polymerase chain reaction, or in-situ hybridization assessment of archival tissue (primary or metastatic) in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Availability of pathology report from CLIA-certified lab demonstrating positive HPV status by p16 immunohistochemistry (IHC), polymerase chain reaction, or in situ hybridization qualifies for eligibility determination. Analysis of fresh tumor tissue is permitted in cases as per standard of care, where archival tissue is not available. A biopsy purely for research purposes will not be allowed to determine HPV status if not indicated by standard of care or if archival tissue is not available.
• c. Platinum resistance defined as prior progression (radiographic or clinical) either during or within 6 months following completion of platinum-based chemotherapy.
• d. Platinum-based therapy as most recent systemic therapy prior to enrollment allowed but not required e. A minimum of 6 patients in the dose expansion cohort must have a PIK3CA mutation.
• Patients may have received any number of lines of prior systemic therapy for locally advanced/metastatic disease.
• Eastern Cooperative Oncology Group performance status \<=1.
• Patient has adequate bone marrow and organ function as defined by the following laboratory values- a. Absolute neutrophil count (ANC) \>= 1.0 x 109/L. b. Platelet count \>= 100 x 109/L. c. Hemoglobin \>= 9.0 g/dL. d. Potassium within normal limits, or corrected with supplements e. International Normalized Ratio (INR) \<=1.5 f. Creatinine clearance \>= 35 mL/min using Cockcroft-Gault formula. g. Total serum bilirubin \<= 2 x upper limit of normal (ULN) (any elevated bilirubin should be asymptomatic at enrollment) except for participants with documented Gilbert's syndrome who may only be included if the total bilirubin \<= 3 x ULN or direct bilirubin \<= 1.5 x ULN).
• h. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<= 2.5 x ULN (or \<= 5 x ULN if liver metastases are present) i. Fasting plasma glucose (FPG) \<= 140mg/dL or 7.7 mmol/L, or hemoglobin A1C (HbA1C)\<= 6.4%.
• Patient is able to swallow oral medications.
• Patient must have archival tissue available for somatic tumor profiling and/or prior somatic tumor profiling with CLIA-certified assay.
• Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in dose escalation. Measurable disease by RECIST 1.1 is required in dose expansion.

You may not qualify if:

• Prior treatment with PI3K-inhibitor.
• Prior known hypersensitivity to any of the excipients of alpelisib.
• Known allergic reaction or poor tolerability to carboplatin.
• Patients with uncontrolled central nervous system (CNS) metastatic involvement. However, patients with metastatic CNS tumors may participate in this study if the patient is-
• \> 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment.
• Clinically stable with respect to the CNS tumor at the time of screening.
• Not receiving steroid therapy.
• Not receiving anti-convulsive medications that were started for brain metastases.
• Patients who have received prior systemic anti-cancer treatment within 4 weeks or 5 half-lives prior to starting study treatment, whichever is shorter.
• Patients with a prior or concurrent malignancy whose natural history or treatment have the potential to interfere with the safety or efficacy assessment of this clinical trial.
• Patients who have received radiotherapy \<=2 weeks prior to starting study drugs, with exception of palliative radiotherapy, who have not recovered from side effects of such therapy to baseline or Grade \<= 1 and/or from whom \>= 30% of the bone marrow was irradiated.
• Patient is currently receiving warfarin or other coumarin-derived anti-coagulant, for treatment, prophylaxis, or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), fondaparinux, or other oral anticoagulants is allowed.
• Patients who have undergone major surgery \<= 4 weeks prior to starting study treatment or who have not recovered from side effects of such procedure.
• Clinically significant cardiac disease or impaired cardiac function, such as-
• Congestive heart failure (CHF) requiring treatment (New York Heart Association (NYHA) Grade \>= 2) or left ventricular ejection fraction (LVEF) \< 50% as determined by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening.

Sponsors & Collaborators

• Pamela Munster: lead
• Novartis: collaborator

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Alpelisib; Carboplatin; Pyruvic Acid

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Pyruvates; Keto Acids; Carboxylic Acids

Study Officials

• Pamela Munster, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 21, 2022
• First Posted: July 25, 2022
• Study Start: November 1, 2022
• Primary Completion (Estimated): April 30, 2028
• Study Completion (Estimated): April 30, 2028
• Last Updated: December 27, 2022

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share