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

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

Study Overview

• Status: Recruiting
• Conditions: Adenocarcinoma; Non-small Cell Lung Cancer; Stage IV
• Intervention / Treatment: Drug: Rigosertib; Drug: Nivolumab

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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Rajwanth Veluswamy, MD, MSCR; Phone Number: (212) 824-8580; Email: rajwanth.veluswamy@mssm.edu
• Study Contact Backup: Name: Vruti Virani; Email: vruti.virani@mssm.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Icahn School of Medicine at Mount Sinai
      • Contact: Rajwanth Veluswamy, MD, MSCR; Phone Number: 212-824-8580; Email: rajwanth.veluswamy@mssm.edu
      • Principal Investigator: Rajwanth Veluswamy, MD, MSCR
      • Contact: Vruti Virani; Email: vruti.virani@mssm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximal Tolerated Dose (MTD)	MTD is defined as the highest dose for which at most 1 patient out of 6 experiences a dose-limiting toxicity (DLT)	DLTs will be evaluated at the end of Cycle 1 (each cycle is 28 days)
Overall Response Rate (ORR)	ORR is defined as achieving an objective response of either complete response or partial response	2 years

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Collaborators: Bristol-Myers Squibb; Onconova Therapeutics, Inc.
• Investigators: Principal Investigator: Rajwanth Veluswamy, MD, MSCR, Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2020
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: February 5, 2020
• First Submitted That Met QC Criteria: February 7, 2020
• First Posted (Actual): February 10, 2020

Study Record Updates

• Last Update Posted (Estimate): May 11, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Nivolumab; Immunotherapy; Metastatic; KRAS; Rigosertib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Nivolumab; ON 01910
• Other Study ID Numbers: GCO 19-2243

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication.
• IPD Sharing 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).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No