A Study Evaluating the Efficacy and Safety of Biomarker-Driven Therapies in Patients With Persistent or Recurrent Rare Epithelial Ovarian Tumors

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of multiple biomarker-selected treatments in patients with persistent or recurrent rare epithelial ovarian, fallopian tube, or primary peritoneal tumors. Enrollment will take place in two phases: a preliminary phase followed by a potential expansion phase.

Official Title
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A Phase II, Open-Label, Multicenter, Platform Study Evaluating the Efficacy and Safety of Biomarker-Driven Therapies in Patients With Persistent or Recurrent Rare Epithelial Ovarian Tumors

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Ipatasertib
* Drug: Cobimetinib
* Drug: Trastuzumab Emtansine
* Drug: Atezolizumab
* Drug: Bevacizumab
* Drug: Paclitaxel
* Drug: Giredestrant
* Drug: Abemaciclib
* Drug: Inavolisib
* Drug: Palbociclib
* Drug: Letrozole
* Drug: Olaparib
* Drug: Luteinizing Hormone-Releasing Hormone (LHRH) Agonists
* Drug: Cyclophosphamide
* Drug: Inavolisib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Persistent or recurrent EOC that meets the following criteria: Histologically confirmed non-high-grade serous, non-high-grade endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer, including but not limited to low-grade serous ovarian carcinoma, clear cell carcinoma, mucinous carcinoma, carcinosarcoma, undifferentiated carcinoma, seromucinous carcinoma, malignant Brenner tumors, Grades 1 or 2 endometrioid carcinoma, mesonephric-like adenocarcinoma and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Disease that is not amenable to curative surgery Measurable disease (at least one target lesion) according to RECIST v1.1 Previous treatment with one to four lines of therapy, at least one of which was platinum-based. Hormonal therapy does not count as a line of therapy. Platinum-resistant disease, defined as disease progression during or within 6 months of last platinum therapy, with the following exception: Participants with primary platinum-refractory disease are excluded. Submission of a representative tumor specimen that is suitable for next-generation sequencing (NGS) testing and estrogen receptor immunohistochemistry (ER IHC) to determine treatment arm assignment and for central pathology review. Submission of the local pathology report and, if available, any associated stained slides that supported the local diagnosis of the histology (to be used for central pathology review) Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Adequate hematologic and end-organ function For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs (if applicable) In addition to the general inclusion criteria above, participants must meet all of the arm-specific inclusion criteria for the respective arm General Exclusion Criteria: Pregnant or breastfeeding, or intending to become pregnant or breastfeed during the study Primary platinum-refractory disease, defined as progression during or within 4 weeks after the last dose of the first-line platinum treatment Histologic diagnosis of high-grade serous or high-grade endometrioid ovarian, fallopian tube, or primary peritoneal cancer Current diagnosis of solely borderline epithelial ovarian tumor Current diagnosis of non-epithelial ovarian tumors Current diagnosis of synchronous primary endometrial cancer Prior history of primary endometrial cancer, with the following exception: a prior diagnosis of primary endometrial cancer is permitted if it meets all of the following conditions: Stage IA, no lymphovascular invasion, International Federation of Gynecology and Obstetrics Grade 1 or 2, not a high-grade subtype. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures Symptomatic, untreated, or actively progressing CNS metastases Severe infection within 4 weeks prior to initiation of study treatment Treatment with chemotherapy, radiotherapy, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, or investigational therapy within 28 days prior to initiation of study treatment Treatment with hormonal therapy within 14 days prior to initiation of study treatment In addition to the general exclusion criteria above, participants can not meet any of the arm-specific exclusion criteria for the respective arm

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Ipatasertib + Paclitaxel (PIK3CA/AKT1/PTEN-altered tumors)<br>Participants in the Ipatasertib + Paclitaxel arm will receive treatment until unacceptable toxicity or disease progression per RECIST v1.1. | Drug: Ipatasertib<br>* Ipatasertib will be administered by mouth once a day on Days 1-21 of each cycle. (Cycle length = 28 days)<br>* Other names: RO5532961;Drug: Paclitaxel<br>* Paclitaxel will be administered intravenously on Days 1, 8, and 15 of each cycle. (Cycle length=28 days)<br>|
| Experimental: Cobimetinib (BRAF/NRAS/KRAS/NF1-altered tumors)<br>Participants in the Cobimetinib arm will receive treatment until unacceptable toxicity or disease progression per RECIST v1.1. | Drug: Cobimetinib<br>* Cobimetinib will be administered by mouth once a day on Days 1-21 of each cycle. (Cycle length=28 days)<br>* Other names: RO5514041;|
| Experimental: Trastuzumab Emtansine (ERBB2-amplified/mutant tumors)<br>Participants in the Trastuzumab Emtansine arm will receive treatment until unacceptable toxicity or disease progression per RECIST v1.1. | Drug: Trastuzumab Emtansine<br>* Trastuzumab Emtansine will be administered intravenously on Day 1 of each cycle. (Cycle length=21 days)<br>* Other names: RO5304020;|
| Experimental: Atezolizumab + Bevacizumab (Non-matched)<br>Participants in the Atezolizumab + Bevacizumab arm will receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. | Drug: Atezolizumab<br>* Atezolizumab will be administered intravenously on Day 1 of each cycle. (Cycle length=21 days)<br>* Other names: RO5541267, Tecentriq;Drug: Bevacizumab<br>* Bevacizumab will be administered intravenously on Day 1 of each cycle. (Cycle length=21 days)<br>* Other names: RO4876646, Avastin;|
| Experimental: Giredestrant + Abemaciclib (ER+ tumors)<br>Participants in the Giredestrant + Abemaciclib arm will receive treatment until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1. | Drug: Giredestrant<br>* Giredestrant will be administered by mouth once a day on Days 1-28 of each cycle (Cycle length=28 days)<br>Drug: Abemaciclib<br>* Abemaciclib will be administered by mouth twice a day during each 28-day cycle<br>Drug: Luteinizing Hormone-Releasing Hormone (LHRH) Agonists<br>* LHRH agonists are required beginning at least 2 weeks prior to initiation of study treatment for premenopausal or perimenopausal women. Acceptable agents include goserelin or leuprolide; triptorelin is also acceptable. Monthly injections of LHRH agonist are preferred.<br>|
| Experimental: Inavolisib + Palbociclib (PIK3CA-altered tumors)<br>Participants in the Inavolisib + Palbociclib arm will receive treatment until unacceptable toxicity or disease progression per RECIST v1.1. | Drug: Inavolisib<br>* Inavolisib will be administered by mouth once a day on Days 1-28 of each 28-day cycle<br>Drug: Palbociclib<br>* Palbociclib will be administered by mouth once a day on Days 1-21 of each 28-day cycle<br>|
| Experimental: Inavolisib + Palbociclib + Letrozole (ER+ and PIK3CA-altered tumors)<br>Participants in the Inavolisib + Palbociclib + Letrozole arm will receive treatment until unacceptable toxicity or disease progression per RECIST v1.1. | Drug: Inavolisib<br>* Inavolisib will be administered by mouth once a day on Days 1-28 of each 28-day cycle<br>Drug: Palbociclib<br>* Palbociclib will be administered by mouth once a day on Days 1-21 of each 28-day cycle<br>Drug: Letrozole<br>* Letrozole will be administered by mouth once a day on Days 1-28 of each 28-day cycle<br>Drug: Luteinizing Hormone-Releasing Hormone (LHRH) Agonists<br>* LHRH agonists are required beginning at least 2 weeks prior to initiation of study treatment for premenopausal or perimenopausal women. Acceptable agents include goserelin or leuprolide; triptorelin is also acceptable. Monthly injections of LHRH agonist are preferred.<br>|
| Experimental: Inavolisib + Olaparib (Non-matched)<br>Participants in the Inavolisib + Olaparib arm will receive treatment until unacceptable toxicity or disease progression per RECIST v1.1. | Drug: Inavolisib<br>* Inavolisib will be administered by mouth once a day on Days 1-28 of each 28-day cycle<br>Drug: Olaparib<br>* Olaparib will be administered by mouth twice a day on Days 1-28 of each 28-day cycle<br>|
| Experimental: Inavolisib + Giredestrant (ER+ and PIK3CA-altered tumors)<br>Participants in the Inavolisib + Giredestrant arm will receive treatment until unacceptable toxicity or disease progression per RECIST v1.1. | Drug: Giredestrant<br>* Giredestrant will be administered by mouth once a day on Days 1-28 of each cycle (Cycle length=28 days)<br>Drug: Inavolisib<br>* Inavolisib will be administered by mouth once a day on Days 1-28 of each 28-day cycle<br>|
| Experimental: Inavolisib + Bevacizumab (PIK3CA-altered tumors)<br>Participants in the Inavolisib + Bevacizumab arm will receive treatment until unacceptable toxicity or disease progression per RECIST v1.1. | Drug: Bevacizumab<br>* Bevacizumab will be administered intravenously on Day 1 of each cycle. (Cycle length=21 days)<br>* Other names: RO4876646, Avastin;Drug: Inavolisib<br>* Inavolisib will be administered by mouth once a day on Days 1-21 of each 21-day cycle<br>|
| Experimental: Atezolizumab + Bevacizumab + Cyclophosphamide (Non-matched)<br>Participants in the Atezolizumab + Bevacizumab + Cyclophosphamide arm will receive treatment until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. | Drug: Atezolizumab<br>* Atezolizumab will be administered intravenously on Day 1 of each cycle. (Cycle length=21 days)<br>* Other names: RO5541267, Tecentriq;Drug: Bevacizumab<br>* Bevacizumab will be administered intravenously on Day 1 of each cycle. (Cycle length=21 days)<br>* Other names: RO4876646, Avastin;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered by mouth once a day on Days 1-21 of each cycle. (Cycle length = 21 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Objective Response Rate (ORR) | Confirmed ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) (demonstrated on two consecutive occasions >=4 weeks apart), as determined by the investigator according to RECIST v1.1. | Up to approximately 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | DOR is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. | Up to approximately 5 years | 
| Disease Contral Rate (DCR) | DCR is defined as the proportion of participants with a confirmed CR or PR, or stable disease maintained for at least 16 weeks, as determined by the investigator according to RECIST v1.1. | Up to approximately 5 years | 
| Progression Free Survival (PFS) | PFS after start of treatment is defined as the time from start of treatment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. | Up to approximately 5 years | 
| 6-Month PFS Rate | 6-month PFS rate is defined as the proportion of participants who remained alive and progression-free at 6 months after start of treatment, as determined by the investigator according to RECIST v1.1. | Up to 6 month | 
| Overall Survival (OS) | OS after start of treatment is defined as the time from start of treatment to death from any cause. | Up to approximately 5 years | 
| Confirmed ORR as Determined by IRC (Independent Review Committee) | Confirmed ORR, as determined by the IRC according to RECIST v1.1. | Up to approximately 5 years | 
| DOR as Determined by IRC | DOR, as determined by the IRC according to RECIST v1.1 | Up to approximately 5 years | 
| DCR as Determined by IRC | DCR, as determined by the IRC according to RECIST v1.1 | Up to approximately 5 years | 
| PFS as Determined by IRC | PFS, as determined by the IRC according to RECIST v1.1 | Up to approximately 5 years | 
| Percentage of Participants With Adverse Events | Percentage of participants with adverse events. | Up to approximately 5 years |