Clinical Trials /

Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS

NCT03496766

Description:

This Phase II study consists of 2 parts: 1) pre-screening phase and 2) treatment phase. The pre-screening phase will investigate the presence of HRAS mutations in subjects with a histologically or cytologically confirmed diagnosis of squamous non-small cell lung cancer (SQ-NSCLC). Subjects may participate in the pre-screening phase at initial diagnosis or following prior lines of therapy for SQ-NSCLC. The treatment phase will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with locally advanced squamous non-small cell lung cancer (SQ-NSCLC) with HRAS mutations and for whom there is no curative therapy available.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS
  • Official Title: An Open Label Phase II Study of Tipifarnib in Advanced Squamous Non-small Cell Lung Cancer With HRAS Mutations

Clinical Trial IDs

  • ORG STUDY ID: GECP17/04_THOMAS
  • SECONDARY ID: 2017-004822-13
  • SECONDARY ID: KO-IST-003
  • NCT ID: NCT03496766

Conditions

  • Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
TipifarnibZarnestraExperimental Arm

Purpose

This Phase II study consists of 2 parts: 1) pre-screening phase and 2) treatment phase. The pre-screening phase will investigate the presence of HRAS mutations in subjects with a histologically or cytologically confirmed diagnosis of squamous non-small cell lung cancer (SQ-NSCLC). Subjects may participate in the pre-screening phase at initial diagnosis or following prior lines of therapy for SQ-NSCLC. The treatment phase will investigate the antitumor activity in terms of ORR of tipifarnib in subjects with locally advanced squamous non-small cell lung cancer (SQ-NSCLC) with HRAS mutations and for whom there is no curative therapy available.

Detailed Description

      Subject enrolment may proceed with information available on tumor HRAS status previously
      generated during the pre-screening phase, but all subjects must consent to provide tumor
      slides (or tumor tissue block) from a prior diagnostic biopsy for a retrospective testing of
      RAS gene status, including T81C polymorphism, and other potential biomarkers at a central
      facility.

      Tipifarnib will be administered at a starting dose of 900 mg, po, bid daily on days 1-7 and
      15-21 of 28-day treatment cycles. In the absence of unmanageable toxicities, subjects may
      continue to receive tipifarnib treatment for up to 24 months in the absence of disease
      progression and unmanageable toxicity. Treatment may continue beyond 24 months if there is
      documented evidence of continued clinical benefit. At the judgement of the investigator, the
      dose of tipifarnib may be increased to 1,200 mg.

      Tumor assessments will be performed at screening and approximately every 8 weeks for the
      first 6 months (cycles 2, 4, 6) and then every 12 weeks (cycles 9, 12, 15, etc.) until
      disease progression, starting at the end of Cycle 2. Additional tumor assessments may be
      conducted if deemed necessary by the Investigator or for a confirmation of an objective
      response. Subjects who discontinue tipifarnib treatment for reasons other than disease
      progression must continue tumor assessments until disease progression, withdrawal of
      subject's consent to study procedures or initiation of another anticancer therapy.

      Determination of objective tumor response will be performed by the Investigator according to
      the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Electronic copies of tumor
      images may be de-identified of subject's personal information at the clinical sites and
      collected by the Sponsor to undergo an external independent radiological review if the
      sponsor deems it necessary for the final assessment of treatment efficacy. Subjects with a
      solitary site of disease who have experienced a response may be considered for surgical
      resection. Subjects with a best response of a partial response and residual disease after
      salvage surgery will be eligible to continue on study therapy. Information on the duration of
      response to the last prior therapy will be collected.

      Upon disease progression, subjects will be followed approximately every 12 weeks for survival
      until either death or 24 months after accrual in the subject's study cohort has been
      completed, whichever occurs first. Information on subsequent anticancer therapy will be
      collected.

      All subjects will be followed-up for safety during treatment and for approximately 30
      additional days after treatment discontinuation (or until immediately before the
      administration of another anticancer treatment). Additional safety follow up may be conducted
      if unresolved toxicity is present at the End of Treatment visit.
    

Trial Arms

NameTypeDescriptionInterventions
Experimental ArmExperimentalTipifarnib 900 mg, po, bid daily on days 1-7 and 15-21 of 28-day treatment cycles for up to 24 months
  • Tipifarnib

Eligibility Criteria

        Inclusion Criteria:

          1. Subject has a histologically or cytologically confirmed diagnosis of squamous
             non-small cell lung cancer (SQ-NSCLC) for which there is no curative therapy
             available.

          2. Subject has relapsed (progressive disease) or is refractory to one or more prior
             therapies. In the case of therapy received in the adjuvant or neo-adjuvant setting,
             relapse must have occurred within 12 months to be considered prior therapy. Subject
             may have received prior immunotherapy.

          3. Subject has a tumor that carries a missense HRAS mutation. HRAS status may have been
             assessed either in blood, primary tumor tissue, recurrent or metastatic disease.

          4. Subject has consented to provide tumor slides (or tumor tissue blocks) for biomarker
             evaluation. If enrolment in the treatment portion of the study has taken place based
             on HRAS mutant status as assessed using a blood sample, tumor tissue will be used in
             part for confirmation of HRAS mutant tumor status. Confirmation of HRAS mutant status
             in tumor tissue is required for continuation of treatment. All treated subjects will
             be evaluated for safety.

          5. Subject has measurable disease according to RECIST v1.1.

          6. At least 2 weeks since the last systemic therapy regimen prior to enrolment. Subjects
             must have recovered to NCI CTCAE v. 4.03 < Grade 2 from all acute toxicities
             (excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and
             Investigator) or toxicity must be deemed irreversible by the Investigator.

          7. At least 2 weeks since last radiotherapy. If radiation was localized to the only site
             of measurable disease, there must be documentation of disease progression of the
             irradiated site. Subjects must have recovered from all acute toxicities from
             radiotherapy. Subjects may be on a daily dose of corticosteroids (≤ 20mg prednisone or
             equivalent), as part of their management from prior radiotherapy.

          8. ECOG (Eastern cooperative oncology group) performance status of 0 or 1.

          9. Acceptable liver function:

               1. Bilirubin less than 1.5 times upper limit of normal (x ULN); does not apply to
                  subjects with Gilbert's syndrome diagnosed as per institutional guidelines.

               2. AST Aspartate Amino-transferasa (SGOT) and ALT Aspartate-Alanina-transferasa
                  (SGPT) less than 3 x ULN; if liver metastases are present, then ≥ 5 x ULN is
                  allowed.

         10. Acceptable renal function with serum creatinine less than 1.5 x ULN or a calculated
             creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault formula.

         11. Acceptable hematologic status:

               1. ANC (absolut neuthophil count) ≥ 1500 cells/μL.

               2. Platelet count ≥ 100,000/μL.

               3. Hemoglobin ≥ 9.0 g/dL.

         12. Female subjects must be either:

               1. Of non-child-bearing potential (surgically sterilized or at least 2 years
                  post-menopausal); or

               2. If of child-bearing potential, subject must use an adequate method of
                  contraception consisting of two-barrier method or one barrier method with a
                  spermicide or intrauterine device. Both females and male subjects with female
                  partners of child-bearing potential must agree to use an adequate method of
                  contraception for 2 weeks prior to screening, during, and at least 4 weeks after
                  last dose of trial medication. Female subjects must have a negative serum or
                  urine pregnancy test within 72 hours prior to start of trial medication.

               3. Not breast feeding at any time during the study.

         13. Written and voluntary informed consent for the treatment phase understood, signed and
             dated.

        Exclusion Criteria:

          1. Ongoing treatment with an anticancer agent not contemplated in this protocol.

          2. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor.

          3. Any history of clinically relevant coronary artery disease or myocardial infarction
             within the last 3 years, New York Heart Association (NYHA) grade III or greater
             congestive heart failure, cerebro-vascular attack within the prior year, or current
             serious cardiac arrhythmia requiring medication except atrial fibrillation.

          4. Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and
             well controlled for at least 4 weeks prior to Cycle 1 Day 1).

          5. Non-tolerable > Grade 2 neuropathy or evidence of emerging or rapidly progressing
             neurological symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable grade 2
             toxicities are defined as those with moderate symptoms that the patient is not able to
             endure for the conduct of instrumental activities of daily life or that persists ≥ 7
             days.

          6. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1,
             without complete recovery.

          7. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
             therapy. Known infection with HIV, or an active infection with hepatitis B or
             hepatitis C.

          8. Subjects who have exhibited allergic reactions to tipifarnib or structural compounds
             similar to tipifarnib or to the drug product excipients. This includes
             hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, miconazole and
             others in this drug class. Patients with hypersensitivity to these agents will be
             excluded from enrolment.

          9. Concomitant disease or condition that could interfere with the conduct of the study,
             or that would, in the opinion of the Investigator, pose an unacceptable risk to the
             subject in this study.

         10. The subject has legal incapacity or limited legal capacity.

         11. Significantly altered mental status that would limit the understanding or rendering of
             informed consent and compliance with the requirements of this protocol. Unwillingness
             or inability to comply with the study protocol for any reason.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:From the first dose until progression disease, assessed from the first dose until the first assessment at week 6 from the first dose
Safety Issue:
Description:To determine the antitumor activity in terms of objective response rate (ORR) of tipifarnib in subjects with locally advanced unresectable or metastatic, relapsed and/or refractory, squamous non-small cell lung cancer (SQ-NSCLC) with HRAS mutations

Secondary Outcome Measures

Measure:Frequency of HRAS mutations
Time Frame:at the beginning of the study, day -7 to day 0
Safety Issue:
Description:As there is a screening phase where HRAS mutations will be analyzed, the second outcome is to determine the frequency (%) of this mutation in the target population of this study
Measure:Tolerability as Incidence of Treatment-Emergent Adverse Events of Tipifarnib
Time Frame:from the first dose of treatment until 30 days after the last dose of treatment
Safety Issue:
Description:Adverse events will be collected in all the patients in order to now the tolerability of the treatment

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Spanish Lung Cancer Group

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