Pharmacy and Poisons Board: Applications

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Protocol No:

ECCT/24/02/06

Date of Protocol:

16-11-2022

Study Title:	A phase III, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Inavolisib in combination with Phesgo versus placebo in combination with Phesgo as maintenance therapy after first line induction therapy in participants with PIK3CA‐mutated HER2‐positive locally advanced or metastatic breast cancer
Study Objectives:	Primary Objective: To demonstrate PFS superiority of inavolisib in combination with Phesgo over placebo in combination with Phesgo Corresponding Estimand: Population: Participants with PIK3CA-mutated, HER2‑positive ABC, as defined by the inclusion and exclusion criteria in Sections 5.1 and 5.1.1 (FAS) Variable: Time from randomization to the first occurrence of a PFS event assessed by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first) Treatment arms: – Experimental arm: inavolisib 9 mg PO QD on Days 1−21 of each 21‑day cycle in combination with Phesgo subcutaneously every 3 weeks (Q3W) – Control arm: placebo tablets PO QD on Days 1−21 of each 21-day cycle in combination with Phesgo SC Q3W Intercurrent events: – Start of non-protocol anticancer therapy prior to a PFS event – Early discontinuation from study treatment for any reason prior to a PFS event Handling of intercurrent events: A treatment policy with regards to the intercurrent events listed above will be applied for the primary analysis Test: Log-rank test Summary measure: Hazard ratio for PFS Key Secondary Objective To evaluate OS of inavolisib in combination with Phesgo compared to placebo in combination with Phesgo Corresponding Estimand Population: Participants with PIK3CA-mutated, HER2‑positive ABC, as defined by the inclusion and exclusion criteria in Sections 5.1 and 5.1.1 (FAS) Variable: Time from randomization to death from any cause Treatment arms: – Experimental arm: inavolisib 9 mg PO QD on Days 1−21 of each 21‑day cycle in combination with Phesgo SC Q3W – Control arm: placebo tablets PO QD on Days 1−21 of each 21‑day cycle in combination with Phesgo SC Q3W Intercurrent events: – Start of non-protocol anticancer therapy prior to an OS event – Early discontinuation from study treatment for any reason prior to an OS event Handling of intercurrent events: A treatment policy with regards to the intercurrent events listed above will be applied for the primary analysis Test: Log-rank test Summary measure: Hazard ratio for OS Secondary Objective To evaluate the efficacy of inavolisib in combination with Phesgo compared with placebo in combination with Phesgo Corresponding Endpoints ORR (following randomization), defined as the proportion of participants with a CR or PR on two consecutive occasions ≥4 weeks apart, as assessed by the investigator according to RECIST v1.1 DOR (following randomization), defined as the time from the first occurrence of a documented objective response to disease progressionas assessed by the investigator according to RECIST v1.1, or death from any cause (whichever occurs first) CBR (following randomization), defined as the proportion of participants with SD for ≥ 24 weeks or a CR or PR, as assessed by the investigator according to RECIST v1.1 PFS2, defined as the time from randomization to disease progression as assessed by the investigator or death from any cause (whichever occurs first) during or following the first non-protocol mandated anti-cancer treatment Mean and mean changes from baseline score in function and HRQoL by cycle and between treatment arms as assessed through the use of the Functional (Role, Physical) and GHS/QoL scales of the EORTC QLQ-C30 Secondary Objective To evaluate the safety of inavolisib in combination with Phesgo compared with placebo in combination with Phesgo Corresponding Endpoints Incidence and severity of adverse events, with severity determined according to NCI PRO-CTCAE Version 5.0 grading scale grading scale Change from baseline in targeted clinical laboratory test results Secondary Objective To characterize the pharmacokinetics of inavolisib Corresponding Endpoint Plasma concentration of inavolisib at specified timepoints Exploratory Objective To evaluate the efficacy of inavolisib in combination with Phesgo compared with placebo in combination with Phesgo Corresponding Endpoints Mean and mean changes from baseline score in remaining function scales and disease/treatment‑related symptoms by cycle and between treatment arms as assessed by the EORTC QLQ-C30 and EORTC QLQ‑BR23. Mean and mean changes from baseline score in the “worst pain” item from the Brief Pain Inventory‑Short Form (BPI‑SF). Exploratory Objective To evaluate effects of inavolisib in combination with Phesgo compared with placebo in combination with Phesgo on work productivity and activity Corresponding Endpoint Changes in participant reported Work Productivity and Activity Impairment Questionnaire (WPAI) scores at specified timepoints Exploratory Objective To evaluate health utility of participants treated with inavolisib in combination with Phesgo compared with placebo in combination with Phesgo to generate utility scores for use in economic models Corresponding Endpoint Health utility and visual analog score of the European Quality of Life 5-Dimension, 5 Level (EQ‑5D‑5L) questionnaire Exploratory Objective To evaluate the tolerability of inavolisib in combination with Phesgo compared with placebo plus Phesgo from the participants perspective Corresponding Endpoints Presence, frequency of occurrence, severity, and/or degree of interference with daily function of symptomatic treatment toxicities (i.e., nausea, vomiting, diarrhea, rash, fatigue, decreased appetite, mouth or throat sores), as assessed through use of the NCI PRO-CTCAE Proportion of participants reporting each response option at each assessment timepoint by treatment arm for treatment side-effect bother single-item GP5 from the FACT‑G Change from baseline in proportion of participants reporting symptomatic treatment toxicities and treatment side-effect bother, as assessed through use of the PRO‑CTCAE and the overall treatment side‑effect bother single-item GP5, respectively Exploratory Objective To evaluate potential relationships between drug exposure and the efficacy and safety of inavolisib plus Phesgo Corresponding Endpoints Relationship between plasma concentrations or PK parameters for inavolisib and efficacy endpoints at specified timepoints Relationship between plasma concentrations or PK parameters for inavolisib and safety endpoints at specified timepoints Exploratory Objective To evaluate potential relationships between selected covariates and inavolisib exposure when given in combination with Phesgo Corresponding Endpoint Relationship between selected covariates and plasma concentration or PK parameters for inavolisib Exploratory Objective To characterize the pharmacokinetics of trastuzumab and pertuzumab Corresponding Endpoint Serum concentrations of trastuzumab and pertuzumab at specified timepoints Exploratory Objective To evaluate the anti‑drug antibodies (ADA) to trastuzumab, pertuzumab, and rHuPH20
Laymans Summary:	This study will evaluate the efficacy and safety of inavolisib in combination with Phesgo (pertuzumab, trastuzumab, and rHuPH20 injection for subcutaneous use) compared with placebo in combination with Phesgo, as maintenance therapy, after induction therapy in participants with previously untreated HER2-positive advanced breast cancer (ABC).
Abstract of Study:	PROTOCOL NUMBER: WO44263 STUDY NAME: INAVO122 VERSION NUMBER: 1 TEST COMPOUND(S): Inavolisib (RO7113755), Phesgo (pertuzumab, trastuzumab, and hyaluronidase [rHuPH20]; RO7198574) Study WO4423 is a Phase III, multicenter, randomized, double-blind, placebo-controlled global study designed to compare the efficacy and safety of inavolisib in combination with Phesgo with placebo in combination with Phesgo, as maintenance therapy, after first‑line induction therapy in participants with PIK3CA‑mutated, HER2‑positive locally advanced or metastatic breast cancer The study consists of a biomarker screening period, an induction screening (for participants who are either receiving or will receive induction therapy) and maintenance screening period of up to 28 days, a treatment period, a post-treatment follow-up period (which includes a “30‑day safety follow‑up” for all participants, when applicable, a “post‑treatment hyperglycemia follow-up”, and/or a “post-treatment tumor assessment follow‑up with PRO collection”), and a survival follow-up period. All candidates must undergo biomarker screening to assess biomarker eligibility. Only participants who have been centrally determined to have HER2-positive tumors that also harbor a PIK3CA mutation will be eligible for further elegibility screening. Biomarker screening may be performed: 1) prior to induction therapy, 2) while candidates are receiving induction treatment as per SoC or 3) immediately after induction therapy, when applicable. NUMBER OF PATIENTS Approximately 230 participants with PIK3CA-mutated, HER2-positive ABC who have not received previous systemic therapy for their disease other than the induction treatment will be randomized into the maintenance therapy phase of this study (Section 4.1.2 of the protocol). Prior to the randomization into maintenance therapy phase, participants with PIK3CA‑mutated, HER2-positive ABC who have not started or have not completed first‑line induction treatment may be enrolled into the induction therapy phase of this trial (see Section 4.1.1 of the protocol). END OF STUDY The end of this study is defined as the date at which the required number of deaths (109 OS events) for the statistical analysis has been observed. The end of the study is expected to occur approximately 111 months after the first participant is enrolled. In addition, the Sponsor may decide to terminate the study at any time. LENGTH OF STUDY Treatment will continue until disease progression per RECIST v1.1, unacceptable toxicity, death, withdrawal of consent, or study termination by the Sponsor. The total duration of study participation for the first individual randomized can range from 1 day to 111 months, for the last individual randomized it can range from 1 day to 74 months.