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



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

Related Conditions:
  • Lung Adenocarcinoma
Recruiting Status:



Phase 1/Phase 2

Trial Eligibility



  • Brief Title: Rigosertib Plus Nivolumab for KRAS+ NSCLC Patients Who Progressed on First-Line 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

Clinical Trial IDs

  • ORG STUDY ID: GCO 19-2243
  • NCT ID: NCT04263090


  • Non-small Cell Lung Cancer
  • Adenocarcinoma
  • Stage IV


RigosertibRigosertib + Nivolumab
NivolumabRigosertib + Nivolumab


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

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

Trial Arms

Rigosertib + NivolumabExperimentalRigosertib + Nivolumab in metastatic KRAS+ lung adenocarcinoma patients
  • Rigosertib
  • Nivolumab

Eligibility Criteria

        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

          -  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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:2 years
Safety Issue:
Description: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.
Measure:Overall Survival (OS) at MTD
Time Frame:2 years
Safety Issue:
Description: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).


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Icahn School of Medicine at Mount Sinai

Trial Keywords

  • KRAS
  • Metastatic
  • Rigosertib
  • Immunotherapy
  • Nivolumab

Last Updated

July 1, 2020