| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063569 |
| E.1.2 | Term | Metastatic squamous cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the objective response rate (ORR) of tipifarnib in subjects with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations with a VAF≥20% (High VAF population), as assessed by
Independent Review Facility (IRF). |
|
| E.2.2 | Secondary objectives of the trial |
To determine the objective response rate (ORR) of tipifarnib in subjects
with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS
mutations of any VAF (All VAF population), as assessed by IRF.
To determine the Duration of Response (DOR) of tipifarnib in subjects with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations with a VAF≥20% (High VAF population), as assessed by IRF.
To determine the Duration of Response (DOR) of tipifarnib in subjects with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS mutations of any VAF (All VAF population), as assessed by IRF. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Observational cohort SEQ-HN. Study title:
The AIM-HN and SEQ-HN Study: A 2 Cohort, Non-comparative, Pivotal Study Evaluating the Efficacy of Tipifarnib in Patients with Head and Neck Squamous Cell Carcinoma (HNSCC) with HRAS Mutations (AIM-HN) and the Impact of HRAS Mutations on Response to First Line Systemic Therapies for HNSCC (SEQ-HN).
Objective for SEQ-HN study and HRAS mutant population:
To determine if HRAS mutational status is predictive of ORR on first line systemic treatment in patients with recurrent/metastatic HNSCC. To determine if treatment outcomes differ (PFS, DOR) with first line
systemic therapy in patients with recurrent/metastatic HNSCC with and without HRAS mutations.
To describe demographic characteristics in patients with HNSCC with and without HRAS mutations. |
|
| E.3 | Principal inclusion criteria |
AIM-HN
1.At least 18 years of age
2.Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy). Enrollment may
proceed with local diagnosis but all subj. must consent to provide tumor tissue for a central pathology review.
3.Documented treatment failure from most recent prior therapy (e.g. tumor progression, clinical deterioration, or recurrence), and from at least one prior platinum-containing regimen, in any treatment setting. The most recent prior and platinum-based therapy may be the same
regimen. Those subj., who, at the judgment of the investigator, are considered clinically unsuitable to receive standard platinum-containing regimen may also be enrolled and the reason for clinical unsuitability recorded. There is no limit on the number of prior lines of therapy.
4.Known tumor missense HRAS mutation detected by Next Generation Sequencing (NGS) or any other methodology approved by the Sponsor. Variant allele frequency (VAF) needs to be determined and must be available. HRAS status should be assessed on tumor tissue obtained subsequent to the most recent prior therapy so that the most accurate tumor biology is evaluated. If tumor tissue that does not meet this criterion must be used (e.g.risk of new biopsy is too high,patient refuses new biopsy), the investigator should document the reason. Enrollment may proceed with the identification of a missense HRAS mutation using a test preferred by the Investigator and approved by the Sponsor during pre-screening, but all subj. must consent to provide tumor tissue for central HRAS confirmation.
a) At least 59 per protocol subj. must have a VAF ≥20%
b) No more than approx. 21 per protocol subj. may have a VAF of <20%.
5.Measurable disease by RECIST v1.1 that meets the criteria for selection as a target lesion according to RECIST v1.1.
6.At least 2 weeks or 5 half-lives, whichever is longer, since the last systemic therapy regimen prior to C1D1. Last dose of any prior checkpoint inhibitor therapy must have been administered at least 2
weeks prior to C1D1.
7.At least 2 weeks since last radiotherapy. Subj. must have recovered from all acute toxicities from radiotherapy.
8.ECOG perform. status of 0-1.
9.Acceptable liver function:
a)Bilirubin less or equal 1.5 times upper limit of normal (x ULN);
b)AST (SGOT) and ALT (SGPT) less or equal 1.5 x ULN. The subject must meet/continue to meet these criteria at the time of first dosing, as confirmed by analysis within 72 hours of C1D1.
10.Acceptable renal function with either serum creatinine less or equal 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min using the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulas. The subj. must meet/continue to meet these criteria at the
time of first dosing, as confirmed by analysis within 72 hours of C1D1.
11.Acceptable hematologic status:
a)ANC ≥ 1000 cells/μL.
b)Platelet count ≥ 75,000/μL.
c)Hemoglobin ≥ 8.0 g/dL.
The subject must meet/continue to meet these criteria at the time of first dosing, as confirmed by review of analysis performed within 72 hours of C1D1.
12.Female subj. must be:
a)Of non-child-bearing potential (surgically sterilized or at least 2 years
post-menopausal); or
b)If of child-bearing potential, subj. must use a highly effective method of contraception or sexual abstinence. Both females and male subj. with female partners of child-bearing potential must agree to use a highly effective method of contraception from the first dose of tipifarnib, during tipifarnib treatment, and at least 28 days after last dose of tipifarnib for females and 90 days for males. Female subj. must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication.
c)Not breast feeding at any time during the study.
13.Written and voluntary informed consent understood, signed and dated.
SEQ-HN
1.At least 18 years of age
2.Histologically confirmed head and neck cancer (oral cavity, pharynx, larynx, sinonasal, nasopharyngeal, or unknown primary) of squamous histology.
3.HRAS wildtype (i.e. have no identified tumor missense HRAS mutation) determined by a test preferred by the Investigator and approved by the Sponsor or through central HRAS testing.
4.Will or has received at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC for which there is available outcome information in terms of ORR, or can be determined based on the
subject's records. Subj. who have not yet received or completed at least one systemic anti-cancer therapy for recurrent or metastatic HNSCC must consent to the collection of treatment outcome information and additional f-u contact in order to participate in the SEQ-HN portion of the study.
5.Written and voluntary informed consent understood, signed and dated. |
|
| E.4 | Principal exclusion criteria |
1.Has disease that is suitable for local therapy administered with curative intent.
2.Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g. mucosal melanoma).
3.Known additional malignancy that is progressing or requires active treatment (excluding non-melanoma skin cancer, adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
4.Ongoing treatment with an anticancer agent not contemplated in this protocol (excluding adjuvant hormonal therapy for breast cancer and hormonal treatment for castration sensitive prostate cancer).
5.Prior treatment (at least 1 full treatment cycle) with a arnesyltransferase inhibitor (FTI).
6.Any use of investigational therapy within 2 weeks of Cycle 1 Day 1(C1D1) or 5 half-lives (whichever is longer). Last dose of any prior checkpoint inhibitor therapy must have been administered at least 2 weeks prior to C1D1.
7.Received treatment for unstable angina within prior year, myocardial infarction within the prior year, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring
medication except atrial fibrillation.
8.Non-tolerable Grade 2 or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1. Non-tolerable Grade 2 toxicities are defined as those with moderate symptoms that the subject is not able to endure for the conduct of instrumental activities of daily life or that persists ≥ 7 days.
9.Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery.
10.Active, uncontrolled bacterial, viral or fungal infections requiring systemic therapy including known history of infection with human immunodeficiency virus or an active infection with hepatitis B or
hepatitis C.
11.Subjects who have exhibited allergic reactions to tipifarnib or structural compounds similar to tipifarnib or to its excipients. This includes hypersensitivity to imidazoles, such as clotrimazole,
ketoconazole, miconazole and others in this drug class. Subjects with hypersensitivity to these agents will be excluded from enrollment.
12.Required use of concomitant medications classified as strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4, Table 11) or UDP-glucuronosyltransferase (UGT).
13.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.
14.Female subjects who are pregnant or lactating.
15.Unwillingness or inability to comply with the study protocol for any reason.
SEQ-HN
1.Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (e.g. mucosal melanoma).
2.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.
3.The subject has legal incapacity or limited legal capacity. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the proportion of high VAF subjects with confirmed Objective Response (OR), defined as either Complete Response (CR) or Partial Response (PR), calculated using the mITT analysis set. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor response assessment visit |
|
| E.5.2 | Secondary end point(s) |
The proportion of all VAF subjects with confirmed Objective Response
(OR), defined as either Complete Response (CR) or Partial Response
(PR), calculated using the mITT analysis set.
The duration of response (DOR) in high VAF subjects, calculated using the mITT analysis set.
The duration of response (DOR) in all VAF subjects, calculated using the mITT analysis set. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumor response assessment visit
End of response assessment visit
Follow up visit |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Korea, Republic of |
| Malaysia |
| Taiwan |
| Thailand |
| United States |
| Austria |
| Netherlands |
| Spain |
| Germany |
| Greece |
| Italy |
| Belgium |
| Denmark |
| Norway |
| Russian Federation |
| Ukraine |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of this clinical study is defined as 2 years from enrollment of the last enrolled study subject in AIM-HN. If the last enrolled study subject discontinues treatment within 2 years of study enrollment, the End of Study will occur no earlier than the date of the last enrolled subject’s safety follow-up assessment (End of Treatment visit) performed approximately 30 days after treatment discontinuation or until initiation of another anti-cancer therapy, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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