Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS

An Open Label Phase II Study of Tipifarnib in Advanced Squamous Non-small Cell Lung Cancer With HRAS Mutations

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.

Study Overview

• Status: Terminated
• Conditions: Non Small Cell Lung Cancer
• Intervention / Treatment: Drug: Tipifarnib

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 600 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.

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08041
    • Hospital de La Santa Creu I Sant Pau
  • Barcelona, Spain, 08036
    • H. Clinic i Provincial
  • Barcelona, Spain, 08035
    • H.U.Vall D´Hebrón
  • Ciudad Real, Spain, 13005
    • Hospital Universitario de Ciudad Real
  • Girona, Spain, 17007
    • ICO Girona -H. Dr. Josep Trueta
  • Jaén, Spain, 23007
    • Hospital de Jaen
  • Lugo, Spain, 27003
    • Hospital Lucus Agustí
  • Madrid, Spain
    • H. 12 de Octubre
  • Madrid, Spain, 28006
    • Hospital La Princesa
  • Madrid, Spain, 28222
    • Hospital Puerta de Hierro
  • Málaga, Spain, 29010
    • H. Carlos Haya
  • Palma de Mallorca, Spain, 07198
    • H. Son Llàtzer
  • Salamanca, Spain, 37007
    • Hospital Clinico De Salamanca
  • Sevilla, Spain, 41009
    • Hospital Virgen de La Macrena
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain
    • Hospital La Fe
  • Valencia, Spain, 46014
    • H. General U. de Valencia
  • A Coruña
    • Santiago De Compostela, A Coruña, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago
  • Alicante
    • Alcoy, Alicante, Spain, 03804
      • Hospital Virgen de los Lirios
    • Elche, Alicante, Spain, 03203
      • Hospital General Universitario de Elche
  • Asturias
    • Oviedo, Asturias, Spain
      • Hospital Central de Asturias
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • ICO-Badalona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08908
      • ICO-Hospitalet
  • Castelló
    • Castelló de la Plana, Castelló, Spain, 12002
      • Hospital Provincial de Castellón
  • Madrid
    • Alcorcón, Madrid, Spain, 28922
      • Hospital Universitario Fundación Alcorcón
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Universitario de la Arrixaca
  • Málaga
    • Marbella, Málaga, Spain, 29603
      • Hospital Costa del Sol
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Complejo Hospitalario de Navarra
  • Tarragona
    • Reus, Tarragona, Spain, 43204
      • Hospital Sant Joan de Reus
  • Tenerife
    • La Laguna, Tenerife, Spain, 38320
      • H. Universitario de Canarias

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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. Before enrolment the site must confirm the availability of the tumor sample. If there is no sample available, the trial chair must be contacted for approval. 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 must be sent before starting cycle 2 of treatment, and It 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. If HRAS mutation is not confirmed in tumor but is clearly positive in blood, the trial chair will be contacted for approval and the treatment could be maintained. All treated subjects will be evaluated for safety.

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-transferase (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:

a. ANC (absolut neuthophil count) ≥ 1000 cells/μL. b. Platelet count ≥ 75,000/μL. c. 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. Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) or UDP-glucuronosyltransferase (UGT)
10. 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.
11. The subject has legal incapacity or limited legal capacity.
12. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm; Tipifarnib 600 mg, po, bid daily on days 1-7 and 15-21 of 28-day treatment cycles for up to 24 months	Drug: Tipifarnib; Tipifarnib 600 mg will be administered until progression; Other Names: Zarnestra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response	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. Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions.	From the first dose until progression disease, assessed from the first dose until the first assessment at week 6 from the first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Defined as the time from the start date of treatment TMT as the origin of follow-up and the first progression or death as final date.	From the start of treatment until first progression or death.
Overall Survival	Defined as the length of time from either the date of diagnosis or the start of the treatment that patients diagnosed with the disease are still alive.	From the date of randomization until end of follow up,up to 24 months

Collaborators and Investigators

• Sponsor: Spanish Lung Cancer Group
• Investigators: Study Chair: Luis Paz Ares, MD, Hospital 12 de Octubre

Publications and helpful links

Helpful Links

• Web page of the sponsor where users can find more information about Fundación GECP studies

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2018
• Primary Completion (Actual): October 30, 2022
• Study Completion (Actual): November 9, 2022

Study Registration Dates

• First Submitted: March 13, 2018
• First Submitted That Met QC Criteria: April 5, 2018
• First Posted (Actual): April 12, 2018

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents; Tipifarnib
• Other Study ID Numbers: GECP17/04_THOMAS; 2017-004822-13 (EudraCT Number); KO-IST-003 (Other Identifier: KURA Oncology)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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