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Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS

Primary Purpose

Non Small Cell Lung Cancer

Status
Active
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Tipifarnib
Sponsored by
Spanish Lung Cancer Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non Small Cell Lung Cancer

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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-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:

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.

Sites / Locations

  • Complejo Hospitalario Universitario de Santiago
  • Hospital Virgen de los Lirios
  • Hospital General Universitario de Elche
  • Hospital Central de Asturias
  • ICO-Badalona
  • ICO-Hospitalet
  • Hospital Provincial de Castellón
  • Hospital Universitario Fundación Alcorcón
  • Hospital Universitario de la Arrixaca
  • Hospital Costa del Sol
  • Complejo Hospitalario de Navarra
  • Hospital Sant Joan de Reus
  • H. Universitario de Canarias
  • H.U.Vall D´Hebrón
  • H. Clinic i Provincial
  • Hospital de La Santa Creu I Sant Pau
  • Hospital Universitario de Ciudad Real
  • ICO Girona -H. Dr. Josep Trueta
  • Hospital de Jaén
  • Hospital Lucus Agustí
  • Hospital La Princesa
  • Hospital Puerta de Hierro
  • H. 12 de Octubre
  • H. Carlos Haya
  • H. Son Llàtzer
  • Hospital Clinico de Salamanca
  • Hospital Virgen de La Macrena
  • Hospital Clínico Universitario de Valencia
  • H. General U. de Valencia
  • Hospital La Fe

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Experimental Arm

Arm Description

Tipifarnib 600 mg, po, bid daily on days 1-7 and 15-21 of 28-day treatment cycles for up to 24 months

Outcomes

Primary Outcome Measures

Overall Response Rate
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

Frequency of HRAS mutations
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
Tolerability as Incidence of Treatment-Emergent Adverse Events of Tipifarnib
Adverse events will be collected in all the patients in order to now the tolerability of the treatment

Full Information

First Posted
March 13, 2018
Last Updated
March 29, 2023
Sponsor
Spanish Lung Cancer Group
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1. Study Identification

Unique Protocol Identification Number
NCT03496766
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
May 7, 2018 (Actual)
Primary Completion Date
October 30, 2022 (Actual)
Study Completion Date
July 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Spanish Lung Cancer Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non Small Cell Lung Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Experimental Arm
Arm Type
Experimental
Arm Description
Tipifarnib 600 mg, po, bid daily on days 1-7 and 15-21 of 28-day treatment cycles for up to 24 months
Intervention Type
Drug
Intervention Name(s)
Tipifarnib
Other Intervention Name(s)
Zarnestra
Intervention Description
Tipifarnib 600 mg will be administered until progression
Primary Outcome Measure Information:
Title
Overall Response Rate
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
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
Secondary Outcome Measure Information:
Title
Frequency of HRAS mutations
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
Time Frame
at the beginning of the study, day -7 to day 0
Title
Tolerability as Incidence of Treatment-Emergent Adverse Events of Tipifarnib
Description
Adverse events will be collected in all the patients in order to now the tolerability of the treatment
Time Frame
from the first dose of treatment until 30 days after the last dose of treatment

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. 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. 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. 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: 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. 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: 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: Of non-child-bearing potential (surgically sterilized or at least 2 years post-menopausal); or 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. 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: Ongoing treatment with an anticancer agent not contemplated in this protocol. Prior treatment (at least 1 full treatment cycle) with an FTase inhibitor. 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. Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 4 weeks prior to Cycle 1 Day 1). 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. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1, without complete recovery. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Known infection with HIV, or an active infection with hepatitis B or hepatitis C. 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. Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) or UDP-glucuronosyltransferase (UGT) 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. The subject has legal incapacity or limited legal capacity. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Luis Paz Ares, MD
Organizational Affiliation
Hospital 12 de Octubre
Official's Role
Study Chair
Facility Information:
Facility Name
Complejo Hospitalario Universitario de Santiago
City
Santiago De Compostela
State/Province
A Coruña
ZIP/Postal Code
15706
Country
Spain
Facility Name
Hospital Virgen de los Lirios
City
Alcoy
State/Province
Alicante
ZIP/Postal Code
03804
Country
Spain
Facility Name
Hospital General Universitario de Elche
City
Elche
State/Province
Alicante
ZIP/Postal Code
03203
Country
Spain
Facility Name
Hospital Central de Asturias
City
Oviedo
State/Province
Asturias
Country
Spain
Facility Name
ICO-Badalona
City
Badalona
State/Province
Barcelona
ZIP/Postal Code
08916
Country
Spain
Facility Name
ICO-Hospitalet
City
L'Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08908
Country
Spain
Facility Name
Hospital Provincial de Castellón
City
Castelló de la Plana
State/Province
Castelló
ZIP/Postal Code
12002
Country
Spain
Facility Name
Hospital Universitario Fundación Alcorcón
City
Alcorcón
State/Province
Madrid
ZIP/Postal Code
28922
Country
Spain
Facility Name
Hospital Universitario de la Arrixaca
City
El Palmar
State/Province
Murcia
ZIP/Postal Code
30120
Country
Spain
Facility Name
Hospital Costa del Sol
City
Marbella
State/Province
Málaga
ZIP/Postal Code
29603
Country
Spain
Facility Name
Complejo Hospitalario de Navarra
City
Pamplona
State/Province
Navarra
ZIP/Postal Code
31008
Country
Spain
Facility Name
Hospital Sant Joan de Reus
City
Reus
State/Province
Tarragona
ZIP/Postal Code
43204
Country
Spain
Facility Name
H. Universitario de Canarias
City
La Laguna
State/Province
Tenerife
ZIP/Postal Code
38320
Country
Spain
Facility Name
H.U.Vall D´Hebrón
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
H. Clinic i Provincial
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital de La Santa Creu I Sant Pau
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
Hospital Universitario de Ciudad Real
City
Ciudad Real
ZIP/Postal Code
13005
Country
Spain
Facility Name
ICO Girona -H. Dr. Josep Trueta
City
Girona
ZIP/Postal Code
17007
Country
Spain
Facility Name
Hospital de Jaén
City
Jaén
ZIP/Postal Code
23007
Country
Spain
Facility Name
Hospital Lucus Agustí
City
Lugo
ZIP/Postal Code
27003
Country
Spain
Facility Name
Hospital La Princesa
City
Madrid
ZIP/Postal Code
28006
Country
Spain
Facility Name
Hospital Puerta de Hierro
City
Madrid
ZIP/Postal Code
28222
Country
Spain
Facility Name
H. 12 de Octubre
City
Madrid
Country
Spain
Facility Name
H. Carlos Haya
City
Málaga
ZIP/Postal Code
29010
Country
Spain
Facility Name
H. Son Llàtzer
City
Palma de Mallorca
ZIP/Postal Code
07198
Country
Spain
Facility Name
Hospital Clinico de Salamanca
City
Salamanca
ZIP/Postal Code
37007
Country
Spain
Facility Name
Hospital Virgen de La Macrena
City
Sevilla
ZIP/Postal Code
41009
Country
Spain
Facility Name
Hospital Clínico Universitario de Valencia
City
Valencia
ZIP/Postal Code
46010
Country
Spain
Facility Name
H. General U. de Valencia
City
Valencia
ZIP/Postal Code
46014
Country
Spain
Facility Name
Hospital La Fe
City
Valencia
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://www.gecp.org
Description
Web page of the sponsor where users can find more information about Fundación GECP studies

Learn more about this trial

Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS

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