RRx-001 in Lung Cancer, Ovarian Cancer and Neuroendocrine Tumors Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)

Study Overview
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Brief Summary
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This study is designed to explore the potential of the epigenetic agent RRx-001 to sensitize patients who previously received and now have failed a platinum based doublet regimen. RRx-001 is administered with autologous blood once weekly followed by or in combination with reintroduction of platinum-based doublet therapy.

Detailed Description
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This is an open label, four 'cohort' study for administration of RRx-001 with autologous blood once weekly followed by or in combination with reintroduction of platinum-based doublet therapy according to the treatment schedule listed below. Small cell carcinoma and ovarian cohort participants will be randomized to 1 of 2 treatment arms, respectively. Neuroendocrine and NSCLC patients will be enrolled to single arms. Participants with SCC will receive one of the following; RRx-001 followed by platinum doublet chemotherapy or platinum based chemotherapy alone. HGNEC, RRx-001 followed by platinum doublet chemotherapy. NSCLC, RRx-001 followed by platinum doublet chemotherapy. Participants with Platinum Refractory/Resistant Ovarian and MMMT will receive one of the following, RRx-001 followed by platinum doublet chemotherapy or chemotherapy alone. Approximately 213 participants will be enrolled.

Official Title
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A Phase II Study of RRx-001 in Platinum Refractory/Resistant Small Cell Carcinoma, EGFR TKI Resistant EGFR+ T790M Negative Non-Small Cell Lung Cancer, High Grade Neuroendocrine Tumors and Resistant/Refractory Ovarian Cancer Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)

Conditions
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Small Cell Carcinoma, Carcinoma, Non-Small-Cell Lung, Neuroendocrine Tumors, Ovarian Epithelial Cancer

Intervention / Treatment
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* Drug: RRx-001
* Drug: Cisplatin
* Drug: Etoposide
* Drug: Carboplatin
* Drug: Irinotecan
* Drug: Vinorelbine
* Drug: Doxil
* Drug: Gemcitabine
* Drug: Taxane
* Drug: Paclitaxel
* Drug: Nab-Paclitaxel
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients must have histologically or cytologically confirmed advanced or metastatic: Resistant/Refractory Small Cell Carcinoma (SCC) patients in 3rd line or beyond that have previously received platinum or patients in 2nd line with platinum-refractory or platinum-resistant disease EGFR mutated non-small cell lung cancer (NSCLC) that has previously received a first line platinum doublet and all applicable EGFR TKIs Epithelial Ovarian Cancer (EOC), fallopian tube or primary peritoneal cancer and Malignant Mixed Mullerian Tumor (MMMT) of the ovary or uterus. Excludes other non-epithelial ovarian tumors and ovarian tumors with low malignant potential. Patients must have previously received a platinum based regimen for advanced/metastatic disease or have platinum resistant or refractory disease defined as relapse within 6 months. EOC - specific criteria: Patients who progress or have stable disease during first-line treatment or who relapse within 1 month are considered to be 'platinum-refractory'. Patients who respond to primary treatment and relapse within 6 months are considered 'platinum-resistant', and patients who relapse more than 6 months after completion of initial therapy are characterized as 'platinum-sensitive'. Patients who relapse 6-12 months following the end of their initial regimen are classified as 'partially sensitive'. Platinum sensitive patients may be enrolled but must have failed or declined all other lines of FDA approved therapy High-Grade Neuroendocrine Carcinoma (HGNEC), any organ of origin, including a pathology of neuroendocrine features, in patients previously been treated with chemotherapy Although neuroendocrine tumors may be classified differently based on organ of origin, in the context of this protocol they are defined as high grade on the basis of either Aggressive clinical behavior requiring previous treatment with chemotherapy even if histologic features such as the Ki67 index or mitotic rate corresponds with low or intermediate grade. Histologic features: (a) Neuroendocrine tumors of lung origin are considered high grade if in any part of the tumors, there are >10 mitoses/2mm2 or 10 high power field (HPF). Large zones of necrosis are usually present. This includes small cell lung carcinoma and large cell neuroendocrine lung carcinoma. [SCLC will not enroll in the HGNEC cohort.] (b)Neuroendocrine tumors of gastroenteropancreatic origin are considered high grade if in any part of the tumors there are either >20 mitoses/2mm2 or 10 high power field (HPF) OR Ki67. Radiographically measurable disease by RECIST v1.1 A washout period of 3-weeks from last treatment. Patients must have previously received a platinum based regimen for advanced/metastatic disease and progressed or have platinum resistant or refractory disease defined as relapse within 6 months. Age ≥18 years. Life expectancy of ≥12 weeks. ECOG performance status 0-2. Participants must have adequate organ and marrow function as defined below both prior to administration of RRx-001 and prior to administration of platinum doublet based regimen: Absolute neutrophil count ≥1,500/mcL Platelets ≥100,000/mcL (non-transfused platelet count) Hemoglobin ≥9 g/dL (transfused Hgb allowed) Creatinine ≤1.5 x the upper limit of normal Total bilirubin ≤2.0 x the upper limit of normal or <3.0 xULN if patient has a history of Gilbert's syndrome AST (SGOT)/ALT (SGPT) ≤5 X institutional upper limit of normal if with liver metastases; ≤2.5 X ULN if no liver metastases Patient must consent to the access, review and analysis of previous medical and cancer history, including tumor archival tissue (if available) and imaging data by the sponsor or a third party nominated by the sponsor. Ability to understand and sign a written informed consent document. Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Note: A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been postmenopausal for at least 12 consecutive months Exclusion Criteria Receiving concurrent investigational therapy Symptomatic central nervous system metastasis (e.g., patients requiring increasing doses of steroids) History of needing to permanently discontinue prior platinum doublet-based regimen for toxicity (e.g., cisplatin causing renal impairment, ototoxicity, or severe neuropathy). Known severe hypersensitivity to the platinum agent (i.e., carboplatin or cisplatin) or prior partner of platinum agent (i.e., etoposide for SCC and HGNEC; nab-paclitaxel, paclitaxel, or pemetrexed for NSCLC; paclitaxel, pegylated liposomal doxorubicin, docetaxel or gemcitabine for ovarian) planned for the platinum therapy period. If the patient has had prior hypersensitivity reaction to the drug partner of platinum, a patient may enroll as long as it is acceptable to treat with platinum and one of the alternative chemotherapy partner agents. Any significant medical diseases or conditions, as assessed by the investigators and sponsor that would substantially increase the medical risks of participating in this study (i.e., uncontrolled diabetes, NYHA II-IV congestive heart failure, myocardial infarction within 6 months of study, severe chronic pulmonary disease or active uncontrolled infection, uncontrolled or clinically relevant pulmonary edema). Pregnant or nursing

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Small Cell Lung Cancer (Arm 1)<br>RRx-001 weekly for 3 weeks followed by up to 4 cycles of carboplatin or cisplatin plus etoposide and then RRx-001 and carboplatin or cisplatin (for patients with stable disease (SD) or better at discontinuation of platinum). | Drug: RRx-001<br> <br> Drug: Cisplatin<br> <br> Drug: Etoposide<br> <br> Drug: Carboplatin<br> <br> |
| Active Comparator: Small Cell Lung Cancer (Arm 2)<br>Carboplatin or cisplatin plus etoposide or irinotecan or vinorelbine until progression or intolerable toxicity | Drug: Cisplatin<br> <br> Drug: Etoposide<br> <br> Drug: Carboplatin<br> <br> Drug: Irinotecan<br> <br> Drug: Vinorelbine<br> <br> |
| Experimental: Non Small Cell Lung Cancer<br>RRx-001 weekly for 3 weeks followed by up to 6 cycles of cisplatin or carboplatin plus paclitaxel or nab-paclitaxel or pemetrexed and then RRx-001 maintenance (for patients with stable disease or better at discontinuation of platinum). | Drug: RRx-001<br> <br> Drug: Cisplatin<br> <br> Drug: Carboplatin<br> <br> Drug: Paclitaxel<br> <br> Drug: Nab-Paclitaxel<br> <br> Drug: Pemetrexed<br> <br> |
| Experimental: Neuroendocrine tumors<br>RRx-001 weekly until progression followed by up to 6 cycles of carboplatin or cisplatin plus etoposide and then RRx-001 maintenance (for patients with stable disease or better at discontinuation of platinum). | Drug: RRx-001<br> <br> Drug: Cisplatin<br> <br> Drug: Etoposide<br> <br> Drug: Carboplatin<br> <br> |
| Experimental: Ovarian epithelial cancer (Arm 1)<br>RRx-001 weekly for 2 weeks followed by 2 cycles of Carboplatin chemotherapy and then RRx-001/Carboplatin maintenance (for patients with stable disease or better at discontinuation of platinum). | Drug: RRx-001<br> <br> Drug: Carboplatin<br> <br> |
| Active Comparator: Ovarian epithelial cancer (Arm 2)<br>Carboplatin, Etoposide, Doxil, Gemcitabine or Vinorelbine or Taxane until progression or intolerable toxicity | Drug: Etoposide<br> <br> Drug: Carboplatin<br> <br> Drug: Vinorelbine<br> <br> Drug: Doxil<br> <br> Drug: Gemcitabine<br> <br> Drug: Taxane<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | the time from enrollment until the time of death from any cause or last follow-up. Patients will be followed clinically as outlined in the treatment schedule and will be followed off study for death. | up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The proportion of patients who achieve a reduction in the sum of target lesions by 30% following the re-administration of chemotherapy. Radiographic assessment of disease burden will be evaluated by CT and disease RR will be documented using RECIST v1.1. | 12 weeks | 
| Disease Control Rate (DCR) | The percentage of patients who have achieved complete response, partial response and stable disease (as per RECIST v1.1). | 12weeks | 
| Progression Free Survival (PFS) | the time from enrollment to the time of the first radiographic documentation of objective progression as defined by RECIST v1.1 or death from any cause. | 12 weeks | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability of platinum doublet therapy post RRx-001 |  | 12 weeks | 
| Changes in the level of serum biomarkers will be calculated and treatment samples will be compared to baseline samples using one-sample tests (e.g., paired t test or Wilcoxon signed rank test). |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epigenetics, resensitization, Platinum doublets, lung cancer, Ovarian epithelial cancer