Evaluation of zAvatar Test-Guided Therapeutic Decisions Versus Standard of Care in Relapsed Ovarian Cancer and Metastatic Breast Cancer with Drug Combination

The primary objective of this study is to evaluate the **zAvatar-test** as a predictive model of treatment efficacy to aid therapeutic decisions in patients with relapsed ovarian cancer and metastatic breast cancer with malignant pleural effusion and/or ascites. This is clinically relevant as it aims to improve treatment outcomes by tailoring therapeutic decisions based on predictive testing. The study will compare the Progression Free Survival (PFS) of patients with relapsed ovarian cancer and metastatic breast cancer treated according to zAvatar-test-based therapeutic decisions versus those treated according to clinical-choice (standard of care).

Secondary objectives include:

• Comparing the Overall Survival (OS) of patients with relapsed ovarian cancer and metastatic breast cancer treated according to zAvatar-test-based therapeutic decisions versus those treated according to clinical-choice.
• Confirming the predictive value of the zAvatar-test by comparing patient clinical response with the response in its matching zAvatar-test, determining specificity, sensitivity, and predictive values.
• Comparing Health Care Sources (HCS) utilization, such as emergency room visits and hospitalizations, for patients treated according to zAvatar-test-based decisions versus clinical-choice.
• Studying clonal and tumor microenvironment diversity, as well as signaling pathways in multi-resistant/multi-sensitive tumors and responders/non-responders at the transcriptomic level, to identify new biomarkers and potential therapeutic targets.

The clinical trial involves a study population exclusively comprising **female** participants, focusing on individuals diagnosed with **breast cancer** and **ovarian cancer**. The age range for participants is 18 years and older, ensuring that all individuals are adults capable of providing informed consent. The trial does not include any vulnerable populations. Participants are required to have a measurable disease as per RECIST 1.1 criteria and an ECOG performance status of 0-2, indicating they are in a condition suitable for treatment. The study targets women with relapsed ovarian cancer, specifically those with inoperable high-grade serous carcinoma or high-grade endometrioid cancer, and women with metastatic breast cancer characterized by malignant pleural effusion or ascites. The trial population was selected based on their ability to understand study procedures and provide informed consent, as well as their medical condition and treatment history. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. Key inclusion criteria include adequate bone marrow, coagulation, liver, renal, and cardiac functions to allow treatment, and the presence of at least two treatment options to be tested according to guidelines.

The clinical trial is designed to evaluate the efficacy of the **zAvatar-test** as a predictive model for treatment decisions in patients with relapsed ovarian cancer and metastatic breast cancer. This study employs a **randomized, controlled** design, comparing the progression-free survival (PFS) of patients treated based on the zAvatar-test against those receiving standard care. The trial is expected to commence recruitment on September 2, 2024, and conclude by June 28, 2030, with a maximum treatment period of 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease stage, and performance status. Subsequent visits will involve treatment administration and monitoring of disease progression and response. Follow-up visits will be scheduled to assess primary and secondary endpoints, including PFS, response rate, and overall survival. The end-of-study visit will finalize data collection and evaluate long-term outcomes.

Participant involvement is anticipated to last up to 24 months, contingent on disease progression and treatment response. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or significant protocol deviations. The trial ensures that all treatments are aligned with current clinical guidelines and are considered equivalent options, minimizing additional risks or discomfort to participants. The study focuses on patients with high-volume ascites or malignant pleural effusion, utilizing remaining fluid samples for the zAvatar-test without additional procedures beyond standard clinical practice.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Palbociclib** is provided in a hard capsule form, with a maximum daily dose of 125 mg, administered orally. The treatment period extends up to 24 months. **Capecitabine** is administered as a film-coated tablet, with a maximum daily dose of 2500 mg/m², also taken orally over a similar treatment duration.

**Niraparib** is available as a film-coated tablet, with a maximum daily dose of 300 mg, administered orally. **Doxorubicin Hydrochloride** is provided as a concentrate for solution for infusion, with a maximum daily dose of 75 mg/m², administered via intravenous infusion. **Topotecan** is available in both capsule and concentrate forms, with a maximum daily dose of 2.3 mg/m² for the capsule and 1.5 mg/m² for the concentrate, both administered orally or via intravenous infusion, respectively.

**Paclitaxel** is administered as a powder for suspension for solution, with a maximum daily dose of 260 mg/m², delivered through intravenous infusion. **Sacituzumab Govitecan** is provided as a powder for concentrate for solution for infusion, with a maximum daily dose of 10 mg/kg, administered intravenously. **Fulvestrant** is available as a solution for injection in a pre-filled syringe, with a maximum daily dose of 500 mg, administered via intramuscular injection.

**Carboplatin** is administered as a concentrate for solution for infusion, with a maximum daily dose of 400 mg/m², delivered intravenously. **Docetaxel** is provided as a concentrate for solution for infusion, with a maximum daily dose of 100 mg/m², administered via intravenous infusion. **Vinorelbine** is available in both capsule and concentrate forms, with a maximum daily dose of 80 mg/m² for the capsule and 30 mg/m² for the concentrate, administered orally or via intravenous infusion, respectively.

**Atezolizumab** is administered as a solution for infusion, with a maximum daily dose of 1680 mg, delivered intravenously. **Cyclophosphamide** is available as a powder for solution for injection and as a coated tablet, with a maximum daily dose of 600 mg/m² for the powder and 300 mg for the tablet, administered via intravenous administration or orally, respectively. **Olaparib** is provided as a film-coated tablet, with a maximum daily dose of 600 mg, administered orally.

**Doxorubicin Hydrochloride, Liposomal** is administered as a concentrate for dispersion for infusion, with a maximum daily dose of 75 mg/m², delivered via intravenous infusion. **Etoposide** is provided as a concentrate for solution for infusion, with a maximum daily dose of 120 mg/m², administered intravenously. **Gemcitabine Hydrochloride** is available as a powder and concentrate for solution for infusion, with a maximum daily dose of 1250 mg/m², delivered via intravenous infusion.

**Ribociclib** is administered as a film-coated tablet, with a maximum daily dose of 600 mg, taken orally. **Bevacizumab** is provided as a concentrate for solution for infusion, with a maximum daily dose of 15 mg/kg, administered intravenously. All treatments are monitored for participant compliance, ensuring adherence to dosing schedules and administration routes.

The efficacy of the clinical trial will be assessed by evaluating the **Progression Free Survival (PFS)** of patients with relapsed ovarian cancer and metastatic breast cancer. The trial will compare the PFS of patients treated according to the zAvatar-test-based therapeutic decision against those treated according to the clinical-choice, which is the standard of care. The primary endpoints include the PFS for both relapsed ovarian cancer and metastatic breast cancer patients. Secondary endpoints will assess the response rate (RR) and overall survival (OS) for both patient groups, as well as the utilization of healthcare services (HCS) between the treatment arms. Additionally, the trial will sequence selected multi-resistant/multi-sensitive responders/non-responders tumors at the transcriptomic level using single-cell RNA sequencing (scRNAseq).

The trial is designed to be a low interventional study, ensuring that no additional risks or discomfort are introduced beyond standard clinical practice. The drugs used in the trial are already authorized and commonly used in clinical practice for the study population. The treatments are considered equivalent options by guidelines and physicians, with decisions on treatment options based on physician experience and patient comorbidities and preferences. The study will utilize remaining liquid samples from ascitic or pleural fluid, which are considered medical waste, for the zAvatar-test, ensuring no additional procedures beyond usual clinical practice.