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Rigosertib Plus Nivolumab for KRAS+ NSCLC Patients Who Progressed on First-Line Treatment

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04263090
Recruitment Status : Recruiting
First Posted : February 10, 2020
Last Update Posted : July 1, 2020
Bristol-Myers Squibb
Onconova Therapeutics, Inc.
Information provided by (Responsible Party):
Rajwanth Veluswamy, Icahn School of Medicine at Mount Sinai

Brief Summary:
A Phase1/2a Study of Rigosertib plus Nivolumab in Stage IV Lung Adenocarcinoma Patients with KRAS Mutation who Progressed on First-Line Treatment

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Adenocarcinoma Stage IV Drug: Rigosertib Drug: Nivolumab Phase 1 Phase 2

Detailed Description:

This is an open-label, dose-escalating Phase I study followed by a Phase 2a dose-expansion phase to study the combination of Rigosertib and Nivolumab in metastatic Kirsten rat sarcoma positive (KRAS+) lung adenocarcinoma patients who have progressed on standard first line treatment. Study patients will have satisfied the inclusion/exclusion criteria enumerated in this protocol. The Phase I dose escalation plan will start with an accelerated titration design (ATD) using single patient cohorts until grade 2 toxicity is experienced. At that point, the ATD will be terminated and the dose escalation will enter a standard 3+3 design based on dose-limiting toxicities (DLT). The MTD (Phase 1 primary endpoint) is defined as the highest dose for which at most 1 patient out of 6 experiences a DLT.

Rigosertib escalation will occur with three dose levels (dose D1: 280mg twice daily; dose D2: 560mg in the morning (qAM), 280mg in the evening (qPM); dose D3: 560mg twice daily; taken by mouth for 21 consecutive days of the 28 day cycle), based on previous dose escalation studies in other malignancies, while Nivolumab dose will be fixed at the standard dose (240mg every 2 weeks, given intravenously).

Once the MTD is determined, an additional planned 12 patients will be enrolled in the expansion phase to further study toxicity and to determine preliminary efficacy endpoints including ORR (phase 2a primary endpoint), PFS, and OS (secondary endpoints) of the combination.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Sequential Assignment
Intervention Model Description:

Dose-escalating Phase I study followed by a Phase 2a dose-expansion phase.

Rigosertib escalation will occur with three dose levels: Dose D1: 280mg twice daily, Dose D2: 560mg qAM, 280mg qPM, Dose D3: 560mg twice daily. Nivolumab will be dosed at the standard fixed dose of 240mg.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase1/2a Study of Rigosertib Plus Nivolumab in Stage IV Lung Adenocarcinoma Patients With KRAS Mutation Who Progressed on First-Line Treatment
Actual Study Start Date : June 29, 2020
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Rigosertib + Nivolumab
Rigosertib + Nivolumab in metastatic KRAS+ lung adenocarcinoma patients
Drug: Rigosertib
Rigosertib will be dosed twice a day for 21 consecutive days, followed by 7 days off treatment (each cycle duration: 28 days). Rigosertib escalation will occur with three dose levels (dose D1: 280mg twice daily; dose D2: 560mg qAM, 280mg qPM; dose D3: 560mg twice daily).

Drug: Nivolumab
Nivolumab will be dosed once ever 2 weeks (twice per 28-day cycle; standard fixed dose of 240mg).

Primary Outcome Measures :
  1. Maximal Tolerated Dose (MTD) [ Time Frame: DLTs will be evaluated at the end of Cycle 1 (each cycle is 28 days) ]
    MTD is defined as the highest dose for which at most 1 patient out of 6 experiences a dose-limiting toxicity (DLT)

  2. Overall Response Rate (ORR) [ Time Frame: 2 years ]
    ORR is defined as achieving an objective response of either complete response or partial response

Secondary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 2 years ]
    Phase 2: PFS is defined as the duration of time from start of treatment to the first occurrence of disease progression or death on study from any cause, whichever occurs earlier.

  2. Overall Survival (OS) at MTD [ Time Frame: 2 years ]
    Phase 2: OS at MTD is defined as the time from the first dose of study treatment to the date of death (whatever the cause).

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

Inclusion criteria

  • Be willing and able to provide written informed consent for the trial.
  • Be at least 18 years of age on the day of signing informed consent.
  • Have a histologically or cytologically confirmed diagnosis of Stage IV metastatic lung adenocarcinoma (AJCC version 8) with mutation analysis by next generation sequencing (NGS) confirming KRAS mutation either at time of diagnosis or at progression on first line treatment.
  • Have progressed on or intolerant of standard of care first-line treatment with anti-programmed death-ligand 1 (PD1) checkpoint inhibitor monotherapy or anti-PD1 checkpoint inhibitor in combination with platinum doublet chemotherapy for Stage IV metastatic lung adenocarcinoma. The last cycle of first-line treatment must occur at least 28 days prior to administration of trial drugs (i.e., washout period)
  • Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesion.
  • Have a life expectancy of at least 3 months.
  • Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  • Have adequate organ function as indicated by the following laboratory values in Table 1. Specimens must be collected within 14 days prior to the start of trial.
  • Patient must be willing and able to provide blood samples (12 green tops tubes, roughly 100mL) at the time points indicated in the Study Calendar.
  • Patient must be willing and able to have core needle biopsies (Goal 4-8 biopsies, final number to be determined by the surgeon and radiologist performing the procedure as safe) of tumor prior to initiation of study drug, and at time points indicated in the Study Calendar.
  • Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and following completion of therapy for 5 months if female and 7 months if male.
  • Female subjects of child-bearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (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 naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Exclusion Criteria

  • Patients may not be receiving any other investigational agents. If received as part of first line treatment, last administration of previous investigational agent must be greater than 4 weeks prior to administration of study drug combination.
  • Patients must not be pregnant or nursing due to the potential for congenital abnormalities or harm to nursing infants.
  • Tumor harbors an epidermal growth factor receptor (EGFR) sensitizing (activating) mutation or an anaplastic lymphoma kinase (ALK) translocation. All other co-mutations will be allowed.
  • Has known untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are without evidence of progression for at least 4 weeks by repeat radiological imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study drug.
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients on chronic steroids (more than 4 weeks at stable dose) equivalent to ≤ 10mg prednisone will not be excluded.
  • Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is acceptable.
  • Has a known additional malignancy that is progressing and/or required active treatment within the past 3 years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical or anal cancer, prostate cancer on stable dose of hormonal therapy without rising prostate-specific antigen (PSA), and breast cancer whom have been treated with curative intent, who may be on hormonal therapy.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
  • HIV positive with detectable viral load, or anyone not on stable anti-viral (HAART) regimen, or with <350 cluster of differentiation 4 (CD4+) T cells/microliter in the peripheral blood. No HIV testing is required.
  • History of allogeneic hematopoietic cell transplantation or solid organ transplantation.
  • Receipt of a live vaccine within 30 days of planned start of study medication
  • History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious pneumonitis that required immunosuppressive doses of glucocorticoids to assist with management. A history of radiation pneumonitis in the radiation field is permitted.
  • Prisoners or subjects who are involuntarily incarcerated.
  • Subjects who are compulsorily detained for treatment of either psychiatric or physical (e.g. infectious disease) illness.

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 identifier (NCT number): NCT04263090

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Contact: Rajwanth Veluswamy, MD, MSCR (212) 824-8580
Contact: Joseph LaValle, BA 2128247376

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United States, New York
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Rajwanth Veluswamy, MD, MSCR    212-824-8580   
Contact: Joseph LaValle, BA    2128247376   
Principal Investigator: Rajwanth Veluswamy, MD, MSCR         
Sponsors and Collaborators
Icahn School of Medicine at Mount Sinai
Bristol-Myers Squibb
Onconova Therapeutics, Inc.
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Principal Investigator: Rajwanth Veluswamy, MD, MSCR Icahn School of Medicine at Mount Sinai
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Responsible Party: Rajwanth Veluswamy, Assistant Professor, Hematology & Medical Oncology, Icahn School of Medicine at Mount Sinai Identifier: NCT04263090    
Other Study ID Numbers: GCO 19-2243
First Posted: February 10, 2020    Key Record Dates
Last Update Posted: July 1, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: All of the individual participant data collected during the trial, after deidentification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Beginning 3 months and ending 5 years following article publication.
Access Criteria: Researchers who provide a methodologically sound proposal.To achieve aims in the approved proposal.Proposals should be directed to xxx@yyy. To gain access, data requestors will need to sign a data access agreement. Data are available for 5 years at a third party website (Link to be included).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Rajwanth Veluswamy, Icahn School of Medicine at Mount Sinai:
Additional relevant MeSH terms:
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Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
ON 01910
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action