Tamoxifen and SUBA-Itraconzole Combination Testing in Ovarian Cancer

Study Overview
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Brief Summary
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The study's purpose is to understand the effects of a new treatment (suba-itraconazole and tamoxifen) in epithelial ovarian cancer. Who is it for? Patients may be eligible to join this study with ovarian cancer resistant to platinum-based chemotherapy agents Study Details: Participants will receive different doses of tamoxifen and suba-itraconazole to determine the optimal combination dose. Participants will be seen by the investigators once a week for the first 3 weeks and then once every 4 weeks. Participant will be reviewed by a clinician and undergo regular blood tests, cardiac monitoring and imaging assessments.

Detailed Description
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A phase 1/2 study of Suba-itraconazole and Tamoxifen in platinum resistant ovarian carcinoma

Official Title
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A Phase I/II Trial Investigating the Tolerability, Toxicity and Efficacy of Tamoxifen and SUBA-Itraconazole in Patients With Platinum Resistant Recurrent Epithelial Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: SUBA-itraconazole
* Drug: Tamoxifen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological-based diagnosis of high grade and low grade epithelial ovarian cancer. Patients with clear cell ovarian cancers are not eligible to participate in this study due to higher risk of thromboemboli which could be increased by Tamoxifen. Platinum resistant ovarian cancer with no more than 4 lines of previous systemic therapy (re-treatment with a previous regimen is only counted as 1 line of therapy). Age > 18 years. Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures Eastern Cooperative Oncology Group Performance Status of 0 or 1 Adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of Cycle 1, defined by the following: Neutrophils (absolute neutrophil count ANC >1.5X10^9/L,) Hemoglobin >9 g/dL Platelet count >100,000/L Serum albumin >3 g/dL Total bilirubin 1.5 ≤the upper limit of normal (ULN) and AST and ALT ≤2.5 XULN, with the following exception: Patients with known Gilbert syndrome who have serum bilirubin ≤3XULN may be enrolled. Patients with documented liver metastasis may have AST and ALT ≤5XULN PTT (or aPTT) and INR ≤1.5XULN (except for patients receiving anticoagulation therapy) Serum creatinine ≤ 1.5XULN or creatinine clearance >50 mL/min based on Cockcroft-Gault glomerular filtration rate estimation: (140 - age) X(weight in kg) X0.85 (if female) 72 X(serum creatinine in mg/dL) Life expectancy of at least 3 months Have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1. Patients without any measurable disease may be enrolled on a case-by-case basis in discussion with study principle investigator At least 4 weeks washout period from previous line of treatment (including hormonal treatment) , 2 weeks from radiotherapy Ability to swallow and retain oral medications (without crushing, dissolving or chewing tablets) Willing and able to comply with all study requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments Exclusion Criteria: Patients with any other prior malignancy from which the patient has been disease free for less than 3 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of any site or any other cancer as approved by study principle investigator Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic or asymptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. History of or current evidence of HIV infection, Viral hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening) Patients with symptomatic central nervous system (CNS) metastasis and/or carcinomatous meningitis. Patients with treated CNS metastases are eligible for this study if not receiving corticosteroids and/or anticonvulsants for at least 7 days prior to first dose of study treatment, and the disease is asymptomatic and radiographically stable for at least 2 weeks after completion of CNS-directed therapy. Patients with untreated stable or asymptomatic brain metastases may be enrolled on a case-by-case basis in discussion with study principal investigator. Patients with existing or past history of deep venous thromboembolism are excluded, unless stable on anticoagulation. Patients with Khorana score of greater than or equal to 3 (see https://www.mdcalc.com/khorana-risk-score-venousthromboembolism- cancer-patients) Known hypersensitivity or contraindication to any component of the study treatment. Inability to comply with study and follow-up procedures. Patients who have not recovered (≤ grade 2) from adverse events related to previous treatments, unless approved by study principle investigator Patients unable to swallow orally administered medications and patients with gastrointestinal impairment that could affect the ability to take or absorption of oral medications including sub-acute or complete bowel obstruction. Participants with uncontrolled intercurrent illness Participants not recovered from all toxicities related to prior anticancer therapies to CTCAE grade<1 apart from alopecia Patients with psychiatric illness/social situations that would limit compliance with study requirements

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
Intervention Model: Sequential Assignment
Interventional Model Description: Dose Escalation (3+3) design with Dose Expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-escalation/ expansion<br>SUBA-itraconazole (oral 150mg twice daily) and escalating dose of Tamoxifen (oral once daily) then expansion cohort | Drug: SUBA-itraconazole<br>* 150 mg BD<br>Drug: Tamoxifen<br>* Dose Escalation: Cohort 1: 20 mg OD Cohort 2: 40 mg OD Cohort 3: 60 mg OD Dose-Expansion: Recommended dose from dose-escalation phase of study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase 2 dose of Tamoxifen in combination with Suba-itraconazole |  | 1 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine overall response rate as determined by RECIST V1.1 and GCIG CA125 response criteria | ORR | 2 years | 
| To determine the duration of response | DOR | 2 years | 
| Incidence of Treatment-Emergent Adverse Events via CTCAE v5.0 | Safety | 2 years | 
| Serum concentration of tamoxifen and derivatives | Cmax | 2 years | 
| Serum concentration of tamoxifen and derivatives | AUC | 2 years | 
| Tissue concentration of tamoxifen and derivatives | mg/g | 2 years | 
| Serum concentration of itraconazole | Cmax | 2 years | 
| Serum concentration of itraconazole | AUC | 2 years | 
| Tissue concentration of itraconazole | mg/g | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian Cancer, Tamoxifen, SUBA-Itraconazole, Platinum resistant