NCT02383927

Phase II Study of Tipifarnib in Squamous Head and Neck Cancer With HRAS Mutations

Completed Phase 2 Results posted Last updated 11 July 2024

What this trial tests

Phase 2 trial testing Tipifarnib in Thyroid Cancer in 63 participants. Completed in 14 December 2020.

Timeline

13 May 2015

Primary endpoint
14 December 2020

14 December 2020

Quick facts

Lead sponsor	Kura Oncology, Inc.
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	63
Start date	13 May 2015
Primary completion	14 December 2020
Estimated completion	14 December 2020
Sites	35 locations across France, Italy, Netherlands, Greece, Belgium, United Kingdom, Germany, South Korea

Drugs / interventions tested

• Tipifarnib — full drug profile →

Conditions studied

• Thyroid Cancer — all drugs for Thyroid Cancer →
• Squamous Cell Carcinoma Head and Neck Cancer (HNSCC) — all drugs for Squamous Cell Carcinoma Head and Neck Cancer (HNSCC) →
• HRAS Mutant Tumor — all drugs for HRAS Mutant Tumor →
• Other Squamous Cell Carcinoma (SCC) With HRAS Mutant Tumor — all drugs for Other Squamous Cell Carcinoma (SCC) With HRAS Mutant Tumor →

Sponsor

Kura Oncology, Inc. — full company profile →

Who can join

18 and older, any sex, with Thyroid Cancer or Squamous Cell Carcinoma Head and Neck Cancer (HNSCC). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Antitumor Activity by Objective Response Rate (ORR) Primary · Up to approximately 3 years

The ORR of tipifarnib was response assessments according to RECIST 1.1. The estimate of the ORR was calculated based on the maximum likelihood estimator (i.e., crude percentage of subjects whose best overall response was complete response \[CR\] or partial response \[PR\]). The estimate of the ORR was accompanied by 2-sided 95% confidence interval (CI). The 95% CI was estimated using the Wilson score test-based method. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Disappearance of all non-tar

Group	Value	95% CI
Cohort 1	0.0	0.0 – 25.9
Cohort 2/Stage 1	0.0	0.0 – 32.4
Cohort 2/Stage 2	43.5	25.6 – 63.2
Cohort 3	28.6	8.2 – 64.1

Number of Subjects That Experienced One or More Treatment-emergent Adverse Events (TEAEs) Secondary · Up to approximately 3 years

An adverse event (AE) was any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. TEAEs were defined as AEs that started on or after the first dose of study drug and within 30 days of the last administration of study drug or immediately before the initiation of any other anticancer therapy. The Investigator was required to grade the severity/ intensity of each AE according to NCI-CTCAE version 4.03. If a severity/intensity of Grade 4 (life-threatening) or 5 (d

TEAEs

Group	Value	95% CI
Cohort 1	13
Cohort 2/Stage 1	10
Cohort 2/Stage 2	30
Cohort 3	10

Serious TEAEs

Group	Value	95% CI
Cohort 1	6
Cohort 2/Stage 1	5
Cohort 2/Stage 2	20
Cohort 3	9

Progression-free Survival (PFS) Secondary · Up to approximately 3 years

PFS was defined as the time from first dose (Cycle 1 Day 1) to either first observation of progressive disease (PD) or occurrence of death due to any cause within 126 days (approximately 2 time-intervals for tumour assessments) of either first administration of tipifarnib or the last tumour assessment. Observation of PD could have been by either documented radiographic progression (i.e., scan results) or documentation of symptomatic or clinical progression agreed upon and documented by investigators. In subjects without a progression date or with a death date more than 126 days after the first

Group	Value	95% CI
Cohort 1	4.6	3.1 – 8.4
Cohort 2/Stage 1	6.4	1.8 – 10.3
Cohort 2/Stage 2	5.5	3.6 – 9.2
Cohort 3	8.0	3.7 – 9.3

Duration of Response (DOR) Secondary · Up to approximately 3 years

DOR was the number of months from start date of PR or CR (whichever response was achieved first) to the first date that PD was documented (in subjects with an objective response). PD was determined by the Investigator using RECIST 1.1. The DOR was right-censored at the date for subjects who achieved CR or PR and met one of the following conditions: 1) when non-protocol anticancer treatment started before documentation of PD, 2) when death prior to documented PD or documented PD after more than 1 missed disease assessment visit, or 3) when alive and did not have documentation of PD before a dat

Group	Value	95% CI
Cohort 2/Stage 2	6.2	3.8 – 14.7
Cohort 3	NA	7.5 – NA

Overall Survival (OS) Secondary · Up to approximately 4 years

An analysis of OS was conducted to estimate median OS time and corresponding 95% CI. OS was defined as the time from first dose (Cycle 1 Day 1) to the occurrence of death due to any cause. In subjects without a death date, the OS was censored on 1) the last date of survival status if alive, 2) a data analysis cut-off date for subjects with no survival status documentation, or 3) the date a subject withdrew consent or was lost to follow-up if there was no additional information. Median and 95% CI were calculated via Kaplan-Meier analysis.

Group	Value	95% CI
Cohort 1	36.7	8.7 – NA
Cohort 2/Stage 1	13.8	5.3 – 29.9
Cohort 2/Stage 2	10.8	7.0 – 14.0
Cohort 3	10.4	6.2 – 16.1

Antitumor Activity - Best Overall Response (BOR) Secondary · Up to approximately 3 years

BOR according to RECIST 1.1. Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.

Group	Value	95% CI
Cohort 1	0
Cohort 2/Stage 1	0
Cohort 2/Stage 2	0
Cohort 3	0
Cohort 1	0
Cohort 2/Stage 1	0
Cohort 2/Stage 2	10
Cohort 3	2
Cohort 1	9
Cohort 2/Stage 1	6
Cohort 2/Stage 2	11
Cohort 3	4
Cohort 1	2
Cohort 2/Stage 1	2
Cohort 2/Stage 2	2
Cohort 3	1

Adverse events — posted to ClinicalTrials.gov

Time frame: All-cause mortality: up to approximately 4 years; serious and other AEs: up to approximately 3 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort 1

Serious: 6/13 (46%)

Deaths: 6/13

Cohort 2/Stage 1

Serious: 5/10 (50%)

Deaths: 9/10

Cohort 2/Stage 2

Serious: 20/30 (67%)

Deaths: 24/30

Cohort 3

Serious: 9/10 (90%)

Deaths: 9/10

Serious adverse events (62 terms)

Reaction	System	Cohort 1	Cohort 2/Stage 1	Cohort 2/Stage 2	Cohort 3
Anaemia	Blood and lymphatic system disorders	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—
Death	General disorders	—	—	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Laryngeal obstruction	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—
Tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Chest pain	General disorders	—	—	—	—
Discomfort	General disorders	—	—	—	—
General physical health deterioration	General disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—
Fracture	Injury, poisoning and procedural complications	—	—	—	—
Wound haemorrhage	Injury, poisoning and procedural complications	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—
Sinus bradycardia	Cardiac disorders	—	—	—	—

Other adverse events (170 terms — click to expand)

Reaction	System	Cohort 1	Cohort 2/Stage 1	Cohort 2/Stage 2	Cohort 3
Anaemia	Blood and lymphatic system disorders	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Fatigue	General disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—
Weight decreased	Investigations	—	—	—	—
Asthenia	General disorders	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—	—	—
Pain	General disorders	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—
White blood cell count decreased	Investigations	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—
Leukocytosis	Blood and lymphatic system disorders	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—
Oral pain	Gastrointestinal disorders	—	—	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—

Most-reported serious reactions: Anaemia, Pneumonia, Death, Hypoxia, Respiratory failure, Laryngeal obstruction, Neutropenia, Acute kidney injury.

Data from ClinicalTrials.gov NCT02383927 adverse events section.

Sponsor's own description

Phase II study to investigate the antitumor activity in terms of objective response rate (ORR) of tipifarnib in subjects with advanced tumors that carry HRAS mutations and for whom there is no standard curative therapy available.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. RAS-targeted therapies: is the undruggable drugged?
   Moore AR, Rosenberg SC, McCormick F, Malek S. · · 2020 · cited 832× · PMID 32528145 · DOI 10.1038/s41573-020-0068-6
2. Emerging strategies to target RAS signaling in human cancer therapy.
   Chen K, Zhang Y, Qian L, Wang P. · · 2021 · cited 164× · PMID 34301278 · DOI 10.1186/s13045-021-01127-w
3. Ras and Rap1: A tale of two GTPases.
   Shah S, Brock EJ, Ji K, Mattingly RR. · · 2019 · cited 161× · PMID 29621614 · DOI 10.1016/j.semcancer.2018.03.005
4. Tipifarnib in Head and Neck Squamous Cell Carcinoma With <i>HRAS</i> Mutations.
   Ho AL, Brana I, Haddad R, Bauman J, et al · · 2021 · cited 152× · PMID 33750196 · DOI 10.1200/jco.20.02903
5. Small molecule inhibitors targeting the cancers.
   Liu GH, Chen T, Zhang X, Ma XL, et al · · 2022 · cited 127× · PMID 36254250 · DOI 10.1002/mco2.181
6. Tipifarnib as a Precision Therapy for <i>HRAS</i>-Mutant Head and Neck Squamous Cell Carcinomas.
   Gilardi M, Wang Z, Proietto M, Chillà A, et al · · 2020 · cited 94× · PMID 32727882 · DOI 10.1158/1535-7163.mct-19-0958
7. Posttranslational Modifications of RAS Proteins.
   Ahearn I, Zhou M, Philips MR. · · 2018 · cited 78× · PMID 29311131 · DOI 10.1101/cshperspect.a031484
8. Drugging the Undruggable: Advances on RAS Targeting in Cancer.
   Molina-Arcas M, Samani A, Downward J. · · 2021 · cited 63× · PMID 34200676 · DOI 10.3390/genes12060899