Small Cell Carcinoma, Carcinoma, Non-Small-Cell Lung, Neuroendocrine Tumors, Ovarian Epithelial Cancer
Conditions
Keywords
Epigenetics, resensitization, Platinum doublets, lung cancer, Ovarian epithelial cancer
Brief summary
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
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.
Interventions
Sponsors
EpicentRx, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 1. 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. 2. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From start of treatment through death for up to 64 months from Start of Treatment. | From 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Assessed up to 49 months | Overall Response Rate (ORR) will be defined as the proportion of patients with a CR or a PR per RECIST v1.1 based upon the best response as assessed; confirmation of response was not required, assessed up to 49 months. |
| Disease Control Rate (DCR) | Assessed up to 49 months | The percentage of patients who have achieved complete response, partial response and stable disease (as per RECIST v1.1), assessed up to 49 months. |
| Progression Free Survival (PFS) | Assessed up to 49 months | Progression-free survival (PFS) will be defined as the elapsed time from the from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 49 months. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at 13 academic medical centers between June 2015 and October 2020. The first participant first visit was June 12, 2015 and the last patient last visit was October 8, 2020.
Pre-assignment details
139 participants provided consent. 118 patients consented under Amendment 01-09. 21 patients were consented on Amendment 10 with 13 randomized in the study. A total of 92 patients under Amendment 01-09 and 13 patients under Amendment 10, combined 107 patients.
Participants by arm
| Arm | Count |
|---|---|
| RRx-001 + Platinum Doublet (A01-09) 4mg RRx-001 once weekly (QW) until progression, followed by up to 6 cycles of platinum doublet chemotherapy | 94 |
| RRx-001 + Platinum + RRx-001 (A10) RRx-001 weekly for 3 weeks followed by up to 6 cycles of platinum doublet chemotherapy and then RRx-001 maintenance (for patients with stable disease (SD) or better at discontinuation of platinum). | 11 |
| Investigator's Choice (A10) Standard of Care Investigator's Choice Control Arm, treatment options of one of the following: carboplatin, etoposide, doxil, gemcitabine, vinorelbine or taxane treatments until progression or intolerable toxicity | 2 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Randomized and Received Treatment | Baseline Drop Out | 3 | 0 | 0 | 0 |
| Randomized and Received Treatment | Death | 10 | 1 | 0 | 0 |
| Randomized and Received Treatment | Protocol Violation | 0 | 1 | 0 | 0 |
| Randomized and Received Treatment | Withdrawal by Subject | 6 | 2 | 0 | 0 |
| Screening | Screen Failure | 24 | 0 | 0 | 8 |
Baseline characteristics
| Characteristic | RRx-001 + Platinum Doublet (A01-09) | Total | Investigator's Choice (A10) | RRx-001 + Platinum + RRx-001 (A10) |
|---|---|---|---|---|
| Age, Continuous | 61.4 years STANDARD_DEVIATION 11.3 | 61.6 years STANDARD_DEVIATION 10.9 | 75.0 years STANDARD_DEVIATION 2.8 | 61.3 years STANDARD_DEVIATION 6.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 88 Participants | 100 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 8 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 10 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 74 Participants | 85 Participants | 2 Participants | 9 Participants |
| Region of Enrollment United States | 94 participants | 107 participants | 2 participants | 11 participants |
| Sex: Female, Male Female | 48 Participants | 56 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 46 Participants | 51 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 89 / 89 | 10 / 10 | 2 / 2 |
| other Total, other adverse events | 89 / 89 | 10 / 10 | 2 / 2 |
| serious Total, serious adverse events | 55 / 89 | 6 / 10 | 2 / 2 |
Outcome results
Primary
Overall Survival
From 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.
Time frame: From start of treatment through death for up to 64 months from Start of Treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RRx-001 + Platinum Doublet (A01-09) | Overall Survival | 6.85 Months |
| RRx-001 + Platinum + RRx-001 (A10) | Overall Survival | 7.6 Months |
| Investigator's Choice (A10) | Overall Survival | 7.5 Months |
Secondary
Disease Control Rate (DCR)
The percentage of patients who have achieved complete response, partial response and stable disease (as per RECIST v1.1), assessed up to 49 months.
Time frame: Assessed up to 49 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RRx-001 + Platinum Doublet (A01-09) | Disease Control Rate (DCR) | 42 Participants |
| RRx-001 + Platinum + RRx-001 (A10) | Disease Control Rate (DCR) | 8 Participants |
| Investigator's Choice (A10) | Disease Control Rate (DCR) | 2 Participants |
Secondary
Overall Response Rate (ORR)
Overall Response Rate (ORR) will be defined as the proportion of patients with a CR or a PR per RECIST v1.1 based upon the best response as assessed; confirmation of response was not required, assessed up to 49 months.
Time frame: Assessed up to 49 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RRx-001 + Platinum Doublet (A01-09) | Overall Response Rate (ORR) | 32 Participants |
| RRx-001 + Platinum + RRx-001 (A10) | Overall Response Rate (ORR) | 3 Participants |
| Investigator's Choice (A10) | Overall Response Rate (ORR) | 1 Participants |
Secondary
Progression Free Survival (PFS)
Progression-free survival (PFS) will be defined as the elapsed time from the from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 49 months.
Time frame: Assessed up to 49 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RRx-001 + Platinum Doublet (A01-09) | Progression Free Survival (PFS) | 5.87 months |
| RRx-001 + Platinum + RRx-001 (A10) | Progression Free Survival (PFS) | 6.50 months |
| Investigator's Choice (A10) | Progression Free Survival (PFS) | 12 months |