Phase II Evaluation of RO7435846 in Combination with Multiple Agents for Biomarker-Positive Advanced or Metastatic Solid Tumors

The primary objective of the TAPISTRY Phase II Platform Trial is to evaluate the **efficacy** of the study treatment in patients with alteration/biomarker-positive advanced or metastatic **solid tumors**. This assessment is based on the Independent Review Committee (IRC)-assessed Objective Response Rate (ORR) for tumor types evaluated by RECIST v1.1. The clinical relevance of this objective lies in its potential to provide insights into the treatment's effectiveness in a broad range of solid tumors, which could inform future therapeutic strategies and improve patient outcomes.

Secondary objectives include: - Evaluating the efficacy of the study treatment in patients with alteration/biomarker-positive advanced or metastatic solid tumors, primary CNS tumors at baseline, and advanced or metastatic neuroblastoma. - Assessing efficacy in a subgroup of patients with alteration/biomarker-positive solid tumors with CNS metastases at baseline. - Evaluating the impact of the study treatment on patient-reported outcomes (PROs) concerning function and symptoms. - Assessing the safety and tolerability of the study treatment. - Characterizing the pharmacokinetics of the study treatment and its metabolites, if applicable. - Evaluating the immune response to the study treatment and the potential effects of anti-drug antibodies (ADAs).

The clinical trial involves a total of **499 participants** diagnosed with advanced or metastatic **solid tumors**. The study population includes both male and female subjects, with an age range spanning from children to adults. Participants are required to have a histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy. The trial includes individuals with measurable disease as defined by specific criteria, and those with a performance status suitable for participation, as determined by age-appropriate scales such as the Eastern Cooperative Oncology Group (ECOG) Performance Status, Karnofsky score, or Lansky score. Participants must demonstrate adequate hematologic and end-organ function and have experienced disease progression on prior treatment or have previously untreated disease with no available acceptable treatment. The trial population was selected based on these criteria, ensuring that participants have adequately recovered from their most recent systemic or local cancer treatment. The study does not specify particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of study treatments in patients with **solid tumors** that are advanced, unresectable, or metastatic. The trial employs a **randomized**, **double-blind**, and **controlled** methodology to ensure the reliability and validity of the results. The trial is expected to run until September 25, 2032, with recruitment having commenced on April 29, 2021. Participants will be involved in the study for a duration that aligns with the trial's endpoints and objectives, which include assessing the **objective response rate** (ORR) as evaluated by an Independent Review Committee (IRC) based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

The sequence of study visits begins with an inclusion (screening) visit, where participants are assessed for eligibility based on criteria such as a confirmed diagnosis of a solid malignancy, measurable disease, and adequate performance status. Follow-up visits are scheduled to monitor the participants' response to the treatment, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit marks the conclusion of the participant's involvement, where final assessments are conducted to evaluate the overall outcomes of the treatment.

Participants are expected to remain in the study for its entire duration unless specific conditions necessitate early termination. These conditions may include significant adverse events, disease progression, or withdrawal of consent. The trial's primary endpoint focuses on the IRC-assessed ORR, while secondary endpoints include the duration of response, clinical benefit rate, progression-free survival, and overall survival. The study also evaluates the incidence and severity of adverse events, as well as the pharmacokinetics of the study treatment. The trial's design and procedures are structured to provide comprehensive data on the efficacy and safety of the investigational treatments for solid tumors.

The clinical trial involves the administration of several **experimental medications**. One of the primary investigational drugs is **GDC-6036**, also known by its sponsor product code **RO7435846**. This compound is a small molecule developed by **GENENTECH, INC.** and is chemically synthesized. The active substance is identified by the chemical name 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one. The pharmaceutical form, dosage, route, and frequency of administration are not specified in the provided data.

Another investigational drug in the trial is **GDC-0077**, with the sponsor product code **RO 711-3755/F08-02**. This small molecule is developed by **F. HOFFMANN-LA ROCHE LTD**. The active substance is chemically synthesized and is known by several synonyms, including PROPANAMIDE, 2-((2-((4S)-4-(DIFLUOROMETHYL)-2-OXO-3-OXAZOLIDINYL)-5,6-DIHYDROIMIDAZO(1,2-D)(1,4)BENZOXAZEPIN-9-YL)AMINO)-, (2S)-. The specific details regarding its pharmaceutical form, dosage, route, and frequency of administration are not provided.

Additionally, the trial includes the investigational drug **RO 5532961/F16-01**, another small molecule from **F. HOFFMANN-LA ROCHE LTD**. The active substance is chemically synthesized, but further details on its administration are not available in the data.

Another compound used in the trial is **RO 710-2122/F17-02**, a small molecule developed by **F. HOFFMANN-LA ROCHE LTD**. The active substance is chemically synthesized, and it is also known by the synonym NMS-1191372. Specifics regarding its administration are not detailed in the provided information.

The trial also involves the use of **RO 761-6992/F01-01**, a small molecule from **F. HOFFMANN-LA ROCHE LTD**. The active substance is chemically synthesized, with synonyms including (1R,3r,5S)-3-(6-((R)-3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,,4-b]pyridin-4-yl)-8-oxabicyclo[3.2.1]octan-3-ol. Details on its administration are not specified.

Another investigational drug is **RO 722-3619/F03-01**, also known as BELVARAFENIB, developed by **GENENTECH, INC.**. This small molecule is chemically synthesized, with the active substance identified as 4-AMINO-N-(1-((3-CHLORO-2-FLUOROPHENYL)AMINO)-6-METHYLISOQUINOLIN-5-YL)THIENO(3,2-D)PYRIMIDINE-7-CARBOXAMIDE. Administration details are not provided.

In addition to the experimental medications, the trial may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not mentioned in the provided data. Participant compliance monitoring and dosing schedules are not detailed in the available information.

The efficacy of the investigational treatment in this clinical trial will be assessed primarily through the **objective response rate (ORR)**, as evaluated by an Independent Review Committee (IRC). The ORR will be determined based on confirmed objective responses, which are defined as responses that are sustained for at least four weeks following initial documentation, in accordance with the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). Secondary efficacy endpoints include IRC-assessed duration of response (DOR), clinical benefit rate (CBR), and progression-free survival (PFS), as well as investigator-assessed ORR, DOR, CBR, and PFS, all measured per RECIST v1.1. Additional secondary endpoints involve assessments of time to central nervous system (CNS) progression, overall survival (OS), and various cohort-specific measures such as CNS-ORR, CNS-DOR, CNS-CBR, and CNS-PFS, evaluated using the Response Assessment in Neuro-Oncology (RANO) criteria and the International Neuroblastoma Response Criteria (INRC).

Patient-reported outcomes will be captured using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, focusing on global health status, physical functioning, and role functioning scores. The incidence, type, and severity of adverse events will be monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Pharmacokinetic parameters, including the concentration of the study treatment at specified timepoints, will also be evaluated. The relationship between anti-drug antibody (ADA) status and efficacy, safety, or pharmacokinetic endpoints will be explored. The trial is designed to provide comprehensive data on the efficacy of the treatment across various parameters, ensuring a robust assessment of its therapeutic potential in patients with advanced or metastatic solid tumors.