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

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ClinicalTrials.gov Identifier: NCT02489903
Recruitment Status : Recruiting
First Posted : July 3, 2015
Last Update Posted : March 6, 2019
Sponsor:
Information provided by (Responsible Party):
EpicentRx, Inc.

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.

Condition or disease Intervention/treatment Phase
Small Cell Carcinoma Carcinoma, Non-Small-Cell Lung Neuroendocrine Tumors Ovarian Epithelial Cancer 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 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 213 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Study Start Date : June 2015
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : July 2020


Arm Intervention/treatment
Experimental: Small Cell Lung Cancer (Arm 1)
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
Drug: Cisplatin
Drug: Etoposide
Drug: Carboplatin
Active Comparator: Small Cell Lung Cancer (Arm 2)
Carboplatin or cisplatin plus etoposide or irinotecan or vinorelbine until progression or intolerable toxicity
Drug: Cisplatin
Drug: Etoposide
Drug: Carboplatin
Drug: Irinotecan
Drug: Vinorelbine
Experimental: Non Small Cell Lung Cancer
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
Drug: Cisplatin
Drug: Carboplatin
Drug: Paclitaxel
Drug: Nab-Paclitaxel
Drug: Pemetrexed
Experimental: Neuroendocrine tumors
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
Drug: Cisplatin
Drug: Etoposide
Drug: Carboplatin
Experimental: Ovarian epithelial cancer (Arm 1)
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
Drug: Carboplatin
Active Comparator: Ovarian epithelial cancer (Arm 2)
Carboplatin, Etoposide, Doxil, Gemcitabine or Vinorelbine or Taxane until progression or intolerable toxicity
Drug: Etoposide
Drug: Carboplatin
Drug: Vinorelbine
Drug: Doxil
Drug: Gemcitabine
Drug: Taxane



Primary Outcome Measures :
  1. Overall Survival [ Time Frame: up to one year ]
    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 Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 12 weeks ]

    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.


  2. Disease Control Rate (DCR) [ Time Frame: 12weeks ]
    The percentage of patients who have achieved complete response, partial response and stable disease (as per RECIST v1.1).

  3. Progression Free Survival (PFS) [ Time Frame: 12 weeks ]
    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.

  4. Number of Participants with Adverse Events as a Measure of Safety and Tolerability of platinum doublet therapy post RRx-001 [ Time Frame: 12 weeks ]
  5. 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). [ Time Frame: 12 weeks ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02489903


Contacts
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Contact: Meaghan Stirn 8588122069 mstirn@epicentrx.com
Contact: Scott Caroen 8588122069 scaroen@epicentrx.com

Locations
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United States, California
Stanford University Recruiting
Palo Alto, California, United States, 94304
Contact: Melanie San Pedro-Salcedo    650-724-1388    msanpedro@stanford.edu   
Principal Investigator: Sukhmani Padda, MD         
United States, Connecticut
VA Connecticut Cancer Center Recruiting
West Haven, Connecticut, United States, 06516
Contact: Jessica Jordan    203-932-5711 ext 3287    jessica.jordan@va.gov   
Principal Investigator: Michal Rose, MD         
United States, Indiana
Memorial Hospital of South Bend Recruiting
South Bend, Indiana, United States, 46601
Contact: Amie Lake    574-647-6784    ALake@beaconhealthsystem.org   
Contact: Mary Jane Danner    574-647-7309    MDanner@beaconhealthsystem.org   
Principal Investigator: Thomas J Reid, MD, PhD         
United States, Kentucky
Baptist Health Recruiting
Lexington, Kentucky, United States, 40503
Contact: Stephanie Cason    859-260-3197    stephanie.cason@bhsi.com   
Contact: Micheal F Stephens    859-260-6456    micheal.stephens@BHSI.com   
Principal Investigator: Arvinda Padmanabhan, MD         
United States, Maryland
Walter Reed National Military Medical Center Recruiting
Bethesda, Maryland, United States, 20889
Contact: Sonja Skeete    301-319-4599    sonja.t.skeete.ctr@mail.mil   
Principal Investigator: Karen Zeman, MD         
United States, Michigan
Henry Ford Allegiance Health Recruiting
Jackson, Michigan, United States, 49201
Contact: Kris Strzalkowski, RN    517-205-1522    KSTRZAL1@hfhs.org   
Contact: Natalie Peterson, RN OCN    (517) 205-1549    npeters8@hfhs.org   
Principal Investigator: Malcolm Trimble, MD         
United States, Missouri
Washington University Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Dan Blume    314-362-0872    dan.blume@wustl.edu   
Principal Investigator: Daniel Morgensztern, MD         
United States, Ohio
University of Cincinnati Cancer Institute Recruiting
Cincinnati, Ohio, United States, 45267
Contact: Lauren Hendricks    513-584-5725    hendrilu@ucmail.uc.edu   
Principal Investigator: John C Morris, MD         
United States, Tennessee
University of Tennessee Medical Center Withdrawn
Knoxville, Tennessee, United States, 37920
United States, Virginia
Virginia Cancer Specialists Recruiting
Fairfax, Virginia, United States, 22031
Contact: Karin Choquette, MSN, RN    703-208-9268    Karin.Choquette@USONCOLOGY.COM   
Principal Investigator: Alexander Spira, MD         
United States, West Virginia
West Virginia University Recruiting
Morgantown, West Virginia, United States, 26506
Contact: Carla Ross, RN    304-581-1158    cjross@hsc.wvu.edu   
Principal Investigator: Patrick Ma, MD         
Sponsors and Collaborators
EpicentRx, Inc.
Investigators
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Study Director: Bryan Oronsky, MD, PhD EpicentRx, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: EpicentRx, Inc.
ClinicalTrials.gov Identifier: NCT02489903     History of Changes
Other Study ID Numbers: RRx001-211-01
First Posted: July 3, 2015    Key Record Dates
Last Update Posted: March 6, 2019
Last Verified: March 2019
Keywords provided by EpicentRx, Inc.:
Epigenetics
resensitization
Platinum doublets
lung cancer
Ovarian epithelial cancer
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Ovarian Epithelial
Neuroendocrine Tumors
Carcinoma, Non-Small-Cell Lung
Carcinoma, Small Cell
Small Cell Lung Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Ovarian Neoplasms
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Carcinoma, Bronchogenic
Bronchial Neoplasms
Gemcitabine