Clinical Trials /

Nivolumab and Temozolomide in Treating Patients With Recurrent or Refractory Small-Cell Lung Cancer or Advanced Neuroendocrine Cancer

NCT03728361

Description:

This phase II trial studies how well nivolumab and temozolomide work in treating patients with small-cell lung cancer that has come back or does not respond to treatment, or neuroendocrine cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab and temozolomide may work better in treating patients with small-cell lung cancer and neuroendocrine cancer.

Related Conditions:
  • Neuroendocrine Carcinoma
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Temozolomide in Treating Patients With Recurrent or Refractory Small-Cell Lung Cancer or Advanced Neuroendocrine Cancer
  • Official Title: A Phase II, Multi-Cohort Trial of Combination Nivolumab and Temozolomide in Recurrent/Refractory Small-Cell Lung Cancer and Advanced Neuroendocrine Tumors

Clinical Trial IDs

  • ORG STUDY ID: OSU-18184
  • SECONDARY ID: NCI-2018-02050
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT03728361

Conditions

  • Grade I Neuroendocrine Carcinoma
  • Grade II Neuroendocrine Carcinoma
  • Grade III Neuroendocrine Carcinoma
  • Metastatic Neuroendocrine Carcinoma
  • Neuroendocrine Carcinoma
  • Recurrent Small Cell Lung Carcinoma
  • Refractory Small Cell Lung Carcinoma
  • Lung Cancer Stage IV
  • Large Cell Neuroendocrine Carcinoma
  • Neuroendocrine Tumors
  • Small Cell Lung Cancer Metastatic
  • Small-cell Lung Cancer

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, temozolomide)
TemozolomideCCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, TemomedacTreatment (nivolumab, temozolomide)

Purpose

This phase II trial studies how well nivolumab and temozolomide work in treating patients with small-cell lung cancer that has come back or does not respond to treatment, or neuroendocrine cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab and temozolomide may work better in treating patients with small-cell lung cancer and neuroendocrine cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the efficacy (using response rate per RECIST v1.1) of nivolumab and
      temozolomide for the treatment of patients with either small cell lung cancer that have
      progressed or recurred after prior platinum-based chemotherapy (cohort 1), or progressive
      metastatic neuroendocrine carcinoma of any grade or primary site in any line of therapy
      (cohort 2).

      SECONDARY OBJECTIVES:

      I. To evaluate the safety profile and toxicity of combination nivolumab and temozolomide as
      per Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0.

      II. To evaluate the progression free survival (PFS) and overall survival (OS) of patients
      treated with combination nivolumab and temozolomide.

      III. To evaluate the central nervous system (CNS) PFS of patients with small cell lung cancer
      (SCLC) treated with nivolumab and temozolomide.

      EXPLORATORY OBJECTIVES:

      I. To determine whether treatment with nivolumab and temozolomide leads to a decrease in
      immune-suppressive cell populations (ie myeloid-derived suppressor cells [MDSC]) in
      peripheral blood.

      II. To determine whether objective response rate (ORR), PFS, OS vary by tumor
      O6-methylguanine deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation at
      baseline.

      III. To determine whether baseline tumor mutational burden is predictive of response to
      therapy in patients with SCLC treated with nivolumab and temozolomide.

      IV. To determine whether changes in blood based mutation burden during treatment may predict
      clinical benefit.

      V. To determine whether a composite immune and tumor cell staining score can be developed
      with or without PD-L1 by immunohistochemistry (IHC) to predict response in the SCLC cohort.

      OUTLINE:

      Patients receive nivolumab intravenously (IV) on day 1 of a 28 day cycle. Patients also
      receive temozolomide orally (PO) on days 1-5. Courses repeat every 28 days in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 8 weeks for
      12 months, then every 12 weeks thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, temozolomide)ExperimentalPatients receive nivolumab IV on day 1 of a 28 day cycle. Patients also receive temozolomide PO on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the trial

          -  For Cohort 1: Have histologically or cytologically-documented diagnosis of advanced
             (metastatic and/or unresectable) small cell lung cancer and have progressed or
             recurred after platinum-based chemotherapy. Eligible patients will be defined as
             follows:

               -  Sensitive disease: Patients who had one previous line of chemotherapy and
                  relapsed after > 90 days of completion of treatment

               -  Refractory disease: Patients with no response to first-line chemotherapy or
                  progression < 90 days after completing treatment.

               -  For cohort 1: maximum of 2 prior lines of therapy is allowed (ie second or third
                  line treatment)

          -  For Cohort 2: Have histologically or cytologically-documented diagnosis of advanced
             (metastatic and/or unresectable) neuroendocrine tumor/carcinoma of any grade (World
             Health Organization [WHO] Grade 1-3) of any origin, in any line of therapy (ie both
             treatment na?ve and pre-treated patients allowed), and have clinical or biochemical or
             radiographic progression in the 12 months prior to study registration. Concomitant use
             of a somatostatin analogue is allowed, as long as patients have been on a stable dose
             for at least 2 months

          -  Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
             1.1.

          -  For Cohort 1: Availability of a recent formalin-fixed, paraffin-embedded (FFPE) tumor
             tissue block. A recently obtained archival FFPE tumor tissue block from a primary or
             metastatic tumor resection or biopsy can be provided if it was obtained within 1 year
             of trial screening. Patients with tumor specimens older than 1 year may still be
             eligible if deemed so by study sponsor. For Cohort 2: archival tissue as above is
             preferred, but not required for trial entry. Verification of tumor burden in the
             biopsy is encouraged. For optimal biomarker results, tumor content should be > 30% of
             total tissue area

          -  Be willing to provide peripheral blood samples at screening and day 1 of cycles 1, 2
             and 3 as well as at progressive disease for correlative studies

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Life expectancy greater than 3 months

          -  Ability to swallow and retain oral medication

          -  Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 28 days of treatment
             initiation)

          -  Platelets >= 100,000 / mcL (performed within 28 days of treatment initiation)

          -  Serum creatinine =< 2.0 x upper limit of normal (ULN) OR measured or calculated
             creatinine clearance (CrCl) (glomerular filtration rate [GFR] can also be used in
             place of creatinine or CrCl) >= 50 mL/min as estimated by Cockcroft and Gault formula
             for subject with creatinine levels > 2 X institutional ULN (performed within 28 days
             of treatment initiation)

               -  Creatinine clearance should be calculated per institutional standard

          -  Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN (performed within 28 days of treatment initiation)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
             ULN OR =< 5 x ULN for subjects with liver metastases (performed within 28 days of
             treatment initiation)

               -  Both values must be in the specified range

          -  Albumin >= 2.5 mg/dL (performed within 28 days of treatment initiation)

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants (performed
             within 28 days of treatment initiation)

          -  Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants (performed within 28 days of treatment initiation)

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication. Subjects should
             agree to ongoing pregnancy testing during the course of the study and after the end of
             study therapy. Female subjects of childbearing potential are those who have not been
             surgically sterilized or have not been free from menses for > 1 year

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy.
             Males must refrain from donating sperm during study participation and for 120 days
             after the last dose of study medication.

        Exclusion Criteria:

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment

          -  Has received prior temozolomide therapy

          -  Prior immunotherapy with checkpoint inhibitors (including antibodies to PD-1, PD-L1,
             or CTLA-4) is not allowed

          -  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

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Hypersensitivity to nivolumab or temozolomide or any of their excipients

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
             baseline) from adverse events due to a previously administered agent

               -  Note: Subjects with =< grade 2 neuropathy due to chemotherapy are an exception to
                  this criterion and may qualify for the study

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting therapy

          -  Has a known additional malignancy that is progressing or requires active treatment

          -  Has symptomatic central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with asymptomatic lesions will be eligible if considered
             appropriate by the treating physician. Subjects with previously treated brain
             metastases may participate provided they are stable (without evidence of progression
             by imaging for at least two weeks prior to the first dose of trial treatment and any
             neurologic symptoms have returned to baseline), have no evidence of new or enlarging
             brain metastases, and are not requiring steroids (or are on a stable or decreasing
             dose of steroids equivalent to 10 mg prednisone or less) for at least 7 days prior to
             trial treatment. This exception does not include carcinomatous meningitis which is
             excluded regardless of clinical stability

          -  Has active autoimmune disease, including myasthenic syndrome, which has required
             systemic treatment in the past 2 years (i.e. with use of disease modifying agents,
             corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine,
             insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
             insufficiency, etc.) is not considered a form of systemic treatment

          -  Has an active infection requiring systemic 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 subject?s
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 5 months (for females) or 7 months (for males) after the last dose of trial
             treatment

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Any condition which in the Investigator?s opinion deems the participant an unsuitable
             candidate to receive study drug
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Time Frame:Up to 3 years
Safety Issue:
Description:Response will be defined by a complete response (CR) or partial response (PR), confirmed or unconfirmed. Response will be defined for patients with measurable disease and who receive at least one dose of combination treatment. Exact binomial 95% confidence intervals for the true PR+CR response rate will be calculated.

Secondary Outcome Measures

Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame:Up to 3 years
Safety Issue:
Description:Attribution to drug, time-of-onset, duration of the event, resolution, and any concomitant medications administered will be recorded. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either ?unrelated? or ?unlikely to be related? to study treatment in the event of an actual relationship developing.
Measure:Progression-free survival (PFS)
Time Frame:The time from allocation to the first documented disease progression according to RECIST 1.1 or death due to any cause, whichever occurs first, assessed up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used.
Measure:Central nervous system (CNS) PFS
Time Frame:The time from allocation to the first documented disease progression within the CNS according to RECIST 1.1, assessed up to 3 years
Safety Issue:
Description:CNS PFS will be measured for patients with relapsed vs refractory small-cell lung cancer (SCLC) in cohort 1. The Kaplan-Meier method will be used.
Measure:Overall survival (OS) of patients
Time Frame:Up to 3 years
Safety Issue:
Description:The Kaplan-Meier method will be used.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dwight Owen

Last Updated