Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS

Non Small Cell Lung Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03496766
• Other study ID #: GECP17/04_THOMAS
• Secondary ID: 2017-004822-13KO
• Status: Terminated
• Phase: Phase 2
• Start date: May 7, 2018
• Est. completion date: November 9, 2022

Study information

• Verified date: March 2024
• Source: Spanish Lung Cancer Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: November 9, 2022
• Est. primary completion date: October 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

Drug:
• Tipifarnib
Tipifarnib 600 mg will be administered until progression

Locations

Country	Name	City	State
Spain	Hospital Universitario Fundación Alcorcón	Alcorcón	Madrid
Spain	Hospital Virgen de los Lirios	Alcoy	Alicante
Spain	ICO-Badalona	Badalona	Barcelona
Spain	H. Clinic i Provincial	Barcelona
Spain	H.U.Vall D´Hebrón	Barcelona
Spain	Hospital de La Santa Creu I Sant Pau	Barcelona
Spain	Hospital Provincial de Castellón	Castelló de la Plana	Castelló
Spain	Hospital Universitario de Ciudad Real	Ciudad Real
Spain	Hospital Universitario de la Arrixaca	El Palmar	Murcia
Spain	Hospital General Universitario de Elche	Elche	Alicante
Spain	ICO Girona -H. Dr. Josep Trueta	Girona
Spain	Hospital de Jaén	Jaén
Spain	ICO-Hospitalet	L'Hospitalet de Llobregat	Barcelona
Spain	H. Universitario de Canarias	La Laguna	Tenerife
Spain	Hospital Lucus Agustí	Lugo
Spain	H. 12 de Octubre	Madrid
Spain	Hospital La Princesa	Madrid
Spain	Hospital Puerta de Hierro	Madrid
Spain	H. Carlos Haya	Málaga
Spain	Hospital Costa del Sol	Marbella	Málaga
Spain	Hospital Central de Asturias	Oviedo	Asturias
Spain	H. Son Llàtzer	Palma de Mallorca
Spain	Complejo Hospitalario de Navarra	Pamplona	Navarra
Spain	Hospital Sant Joan de Reus	Reus	Tarragona
Spain	Hospital Clinico de Salamanca	Salamanca
Spain	Complejo Hospitalario Universitario de Santiago	Santiago De Compostela	A Coruña
Spain	Hospital Virgen de La Macrena	Sevilla
Spain	H. General U. de Valencia	Valencia
Spain	Hospital Clínico Universitario de Valencia	Valencia
Spain	Hospital La Fe	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Spanish Lung Cancer Group

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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

External Links

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