A Study Evaluating Targeted Therapies in Participants Who Have Advanced Solid Tumors With Genomic Alterations or Protein Expression Patterns Predictive of Response

Study Overview
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Brief Summary
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This is a Phase II, multicenter, non-randomized, open-label, multi-arm study designed to evaluate the safety and efficacy of targeted therapies as single agents or in rational, specified combinations in participants with advanced unresectable or metastatic solid tumors determined to harbor specific biomarkers. Patients will be enrolled based on local testing performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalently accredited diagnostic laboratory. The multi-arm structure of the MyTACTIC study allows patients with solid tumors to be treated with a drug or drug regimen tailored to their biomarker identified at screening.

Official Title
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MyTACTIC: An Open-Label Phase II Study Evaluating Targeted Therapies in Patients Who Have Advanced Solid Tumors With Genomic Alterations or Protein Expression Patterns Predictive of Response

Conditions
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Advanced Unresectable or Metastatic Solid Malignancy

Intervention / Treatment
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* Drug: Entrectinib
* Drug: Inavolisib
* Drug: Alectinib
* Drug: Ipatasertib
* Drug: Atezolizumab
* Drug: Trastuzumab Emtansine
* Drug: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf
* Drug: Tucatinib
* Drug: Investigator's Choice of Chemotherapy
* Drug: Paclitaxel
* Drug: Tiragolumab
* Drug: Pralsetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic solid malignancy Positive biomarker results from a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalently accredited diagnostic laboratory and availability of a full report of the testing results. This may be from a tissue or blood sample. Evaluable or measurable disease Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Life expectancy ≥8 weeks Adequate hematologic and end-organ function, as defined in the protocol, obtained within 14 days prior to initiation of study treatment Agrees to take measures to prevent pregnancy in the patient or partner In addition to the general inclusion criteria above, there are treatment-specific inclusion criteria that apply for each respective treatment arm (as detailed in the protocol) Exclusion Criteria: Current participation or enrollment in another therapeutic clinical trial Symptomatic or actively progressing CNS metastases (asymptomatic patients with treated or untreated CNS metastases may be eligible, provided all protocol-defined criteria are met) History of leptomeningeal disease, unless noted otherwise for a specific treatment arm of the study Wide field radiotherapy within 14 days prior to start of study treatment Stereotactic radiosurgery within 7 days prior to start of study treatment Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infections, or any active infection that, in the opinion of the investigator, could impact patient safety Receipt of any anticancer drug/biologic or investigational treatment 21 days prior to Cycle 1, Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1, Day 1 (androgen blockage may be continued for male patients with prostate cancer) Known human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infection with status outside of study-allowed criteria History of or concurrent serious medical condition or abnormality in clinical laboratory tests that precludes the patient's safe participation in and completion of the study or confounds the ability to interpret data from the study History of malignancy other than disease under study within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of study treatment Major surgical procedure, other than for diagnosis, or significant traumatic injury within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or higher), myocardial infarction, or cerebrovascular accident within 3 months prior to enrollment, unstable arrhythmias, or unstable angina Pregnant or breastfeeding, or intending to become pregnant during the study In addition to the general exclusion criteria above, there are treatment-specific exclusion criteria that apply for each respective treatment arm (as detailed in the protocol)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Entrectinib<br>Participants in this treatment arm must have a positive tumor biomarker result for ROS1 gene fusion. | Drug: Entrectinib<br>* Entrectinib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 600 milligrams (mg) per day once a day (QD) until disease progression, intolerable toxicity, or consent withdrawal.<br>* Other names: RO7102122;|
| Experimental: Arm B: Inavolisib<br>Participants in this treatment arm must have a positive tumor biomarker result for PI3KCA activating mutation. | Drug: Inavolisib<br>* Inavolisib will be self-administered by participants orally at home (except on clinic days) at the same time each day, on a starting dose of 9 mg/day QD until disease progression, intolerable toxicity, or consent withdrawal.<br>* Other names: RO7113755;|
| Experimental: Arm C: Alectinib<br>Participants in this treatment arm must have a positive tumor biomarker result for ALK rearrangement tumors. | Drug: Alectinib<br>* Alectinib will be self-administered by participants orally at home (except on clinic days), at the same times each day, on a starting dose of 600 mg twice a day (BID) until disease progression, intolerable toxicity, or consent withdrawal.<br>* Other names: RO5424802;|
| Experimental: Arm D: Ipatasertib<br>Participants in this treatment arm must have a positive tumor biomarker result for either AKT1/2/3 activating mutation or PTEN loss/loss of function. | Drug: Ipatasertib<br>* Ipatasertib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 400 mg QD until disease progression, intolerable toxicity, or consent withdrawal.<br>* Other names: RO5532961;|
| Experimental: Arm E: Atezolizumab + Investigator's Choice of Chemotherapy<br>Participants in this treatment arm must have a positive tumor biomarker result for either tumor mutational burden (TMB) high or microsatellite instability (MSI) high/deficient mismatch repair (dMMR). | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg for participants on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit).<br>* Other names: RO5541267;Drug: Investigator's Choice of Chemotherapy<br>* Chemotherapy will consist of docetaxel, paclitaxel, or capecitabine, as determined by the investigator, and will be administered per the respective package insert and institutional guidelines.<br>|
| Experimental: Arm F: Trastuzumab Emtansine + Atezolizumab<br>Participants in this treatment arm must have a positive tumor biomarker result for ERBB2 mutations or amplification without known TMB high or MSI high/dMMR. | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg for participants on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit).<br>* Other names: RO5541267;Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine will be administered at 3.6 mg per kilogram (kg) of body weight by IV infusion every 21 days (unless dose reduction and/or dose delays are required) until disease progression or unacceptable toxicity.<br>* Other names: RO5304020;|
| Experimental: Arm G: PH FDC SC<br>Participants in this treatment arm must have a positive tumor biomarker result for ERBB2 mutation or amplification without known TMB high or MSI high/dMMR. | Drug: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf<br>* PH FDC SC will be administered subcutaneously (SC) at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab once every 3 weeks.<br>* Other names: RO7198574;|
| Experimental: Arm H: PH FDC SC + Investigator's Choice of Chemotherapy<br>Participants in this treatment arm must have a positive tumor biomarker result for ERBB2 mutation or amplification without known TMB high or MSI high/dMMR. | Drug: Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf<br>* PH FDC SC will be administered subcutaneously (SC) at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab once every 3 weeks.<br>* Other names: RO7198574;Drug: Investigator's Choice of Chemotherapy<br>* Chemotherapy will consist of docetaxel, paclitaxel, or capecitabine, as determined by the investigator, and will be administered per the respective package insert and institutional guidelines.<br>|
| Experimental: Arm I: Trastuzumab Emtansine + Tucatinib<br>Participants in this treatment arm must have a positive tumor biomarker result for ERBB2 mutation or amplification without known TMB high or MSI high/dMMR. | Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine will be administered at 3.6 mg per kilogram (kg) of body weight by IV infusion every 21 days (unless dose reduction and/or dose delays are required) until disease progression or unacceptable toxicity.<br>* Other names: RO5304020;Drug: Tucatinib<br>* Tucatinib 300 mg will be administered orally BID continuously starting from Cycle 1 Day 1 onwards.<br>* Other names: Tukysa™;|
| Experimental: Arm J: Trastuzumab Emtansine + Atezolizumab<br>Participants in this treatment arm must have positive tumor biomarker results for ERBB2 mutation or amplification and TMB high or MSI high/dMMR. | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg for participants on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit).<br>* Other names: RO5541267;Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine will be administered at 3.6 mg per kilogram (kg) of body weight by IV infusion every 21 days (unless dose reduction and/or dose delays are required) until disease progression or unacceptable toxicity.<br>* Other names: RO5304020;|
| Experimental: Arm K: Ipatasertib + Atezolizumab<br>Participants in this treatment arm must have a positive tumor biomarker result for PI3KCA activating mutation. | Drug: Ipatasertib<br>* Ipatasertib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 400 mg QD until disease progression, intolerable toxicity, or consent withdrawal.<br>* Other names: RO5532961;Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg for participants on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit).<br>* Other names: RO5541267;|
| Experimental: Arm L: Ipatasertib + Atezolizumab<br>Participants in this treatment arm must have a positive tumor biomarker result for either AKT1/2/3 activating mutation or PTEN loss/loss of function. | Drug: Ipatasertib<br>* Ipatasertib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 400 mg QD until disease progression, intolerable toxicity, or consent withdrawal.<br>* Other names: RO5532961;Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg for participants on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit).<br>* Other names: RO5541267;|
| Experimental: Arm M: Ipatasertib + Paclitaxel<br>Participants in this treatment arm must have a positive tumor biomarker results for PI3KCA activating mutations and either AKT1/2/3 activating mutation or PTEN loss/loss of function. | Drug: Ipatasertib<br>* Ipatasertib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 400 mg QD until disease progression, intolerable toxicity, or consent withdrawal.<br>* Other names: RO5532961;Drug: Paclitaxel<br>* The dose of paclitaxel is 80 mg/m2 administered by IV infusion on Days 1, 8, and 15 of each 28-day cycle. The paclitaxel infusion will be delivered over at least 60 minutes for each dose per institutional guidelines and administered after the oral dose of ipatasertib.<br>|
| Experimental: Arm N: Atezolizumab + Tiragolumab<br>Participants in this treatment arm must have a positive tumor biomarker result for either TMB high or MSI high/dMMR. | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion at a fixed dose of 1200 mg for participants on Day 1 of each 21-day cycle until unacceptable toxicity or progressive disease (or loss of clinical benefit).<br>* Other names: RO5541267;Drug: Tiragolumab<br>* Following the administration of atezolizumab and an observation period, participants will receive 600 mg tiragolumab at a fixed dose administered by IV infusion on Day 1 of each 21-day cycle.<br>* Other names: MTIG7192A;|
| Experimental: Arm O: Pralsetinib<br>Participants in this treatment arm must have a positive tumor biomarker result for RET fusion. | Drug: Pralsetinib<br>* Pralsetinib will be self-administered by participants orally at home (except on clinic days), at the same time each day, on a starting dose of 400 mg/day (four 100-mg capsules per day) once a day (QD) until disease progression, intolerable toxicity, or consent withdrawal.<br>* Other names: RO7499790;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Confirmed Overall Response, as Assessed by the Investigator According to RECIST v1.1 or According to RANO Criteria for Primary CNS Tumors | RANO = Response Assessment in Neuro-Oncology; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1 | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival, as Determined by the Investigator According to RECIST v1.1 or RANO Criteria |  | Up to 3 years | 
| Duration of Response, as Determined by the Investigator According to RECIST v1.1 or RANO Criteria |  | Up to 3 years | 
| Progression-Free Survival Rate at Every 3 Months, Defined as the Percentage of Participants who are Progression-Free as Determined by the Investigator According to RECIST v1.1 or RANO Criteria |  | At every 3 months until study completion (up to 3 years) | 
| Percentage of Participants with Disease Control, as Determined by the Investigator According to RECIST v1.1 or RANO Criteria |  | Up to 3 years | 
| Incidence and Severity of Adverse Events, with Severity Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) |  | From Baseline until 28 days after the final dose of study drug (up to 3 years) |