Gland and Hormone Related Diseases

All Conditions

Neoplasms

Rare Diseases

Thyroid Diseases

Carcinoma

Thyroid Neoplasms

Thyroid Carcinoma, Anaplastic

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Anaplastic Thyroid Cancer

Antineoplastic Agents

All Drugs and Chemicals

Lenvatinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Participants will receive lenvatinib 24 milligrams (mg) (2 10-mg capsules and one 4-mg capsule) once daily by oral administration at approximately the same time each morning for up to approximately 24 months.

Lenvatinib 24 mg

The primary purpose of the study is to evaluate objective response rate (\[ORR\]: complete response \[CR\] and partial response \[PR\]) by investigator review in participants with anaplastic thyroid cancer (ATC) treated with lenvatinib.

A Phase 2 Trial of Lenvatinib for the Treatment of Anaplastic Thyroid Cancer (ATC)

An Open-Label, Single-Arm, Multicenter, Phase 2 Trial of Lenvatinib for the Treatment of Anaplastic Thyroid Cancer (ATC)

Eisai IPD sharing statement: Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

ORR was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for target lesions. CR was defined as disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of the longest diameters of target lesions, taking as reference the Baseline sum diameters. Confirmation of CR or PR was performed at least 28 days following the initial achievement of the response.

Twelve-week PFS rate was the percentage of participants in the analysis population who remain alive and progression-free at 12 weeks. PFS was defined as the time from the date of beginning of lenvatinib administration to the date of first documentation of confirmed disease progression or death, whichever occurred first. The Kaplan-Meier estimated rate method was used to estimate 12-week PFS, along with the corresponding 95% confidence interval (CI). Participants who were off study due to lost to follow up, withdrew consent, or study terminated by sponsor, had new anti-cancer treatment, had no baseline/post-baseline tumor assessments, or missed 2 or more visits prior to event were censored.

Six-month OS rate was defined as the percentage of participants in the analysis population who are alive at 6 months. OS was defined as the time from the date of beginning of lenvatinib administration until date of death from any cause. The Kaplan-Meier estimated rate method was used to estimate six-month OS, along with the corresponding 95% CI. Participants with last known alive date as study terminated by sponsor were censored.

PFS was defined as the time from the date of beginning of lenvatinib administration to the date of first documentation of confirmed disease progression or death, whichever occurs first. Median PFS was estimated using the Kaplan-Meier method. Participants who were off study due to lost to follow up, withdrew consent, or study terminated by sponsor, had new anti-cancer treatment, had no baseline/post-baseline tumor assessments, or missed 2 or more visits prior to event were censored.

OS was defined as the time from the date of beginning of lenvatinib administration until date of death from any cause. Median OS was estimated using the Kaplan-Meier method. Participants with last known alive date as study terminated by sponsor were censored.

Eisai Inc.

Participants received lenvatinib 24 mg (two 10-mg capsules and one 4-mg capsule), orally, once daily in a 28-days treatment cycle up to disease progression, development of unacceptable toxicity, lost to follow up, withdrawal of consent, participant's choice, pregnancy, or study termination by sponsor (approximately 27 months).

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

The full analysis set included all participants who received at least one dose of lenvatinib.

The study was terminated since overall response rate was 3% (only 1 out of 33 participants had confirmed PR).

Eisai Medical Information

The evaluable analysis set included all participants with histological diagnosis of ATC that was confirmed by central pathology review and who received at least one dose of lenvatinib.

Objective Response Rate (ORR)

Progression-free Survival (PFS) Rate

Overall Survival (OS) Rate

Median PFS

Median OS

Participants received lenvatinib 24 milligram (mg) (two 10-mg capsules and one 4-mg capsule), orally, once daily in a 28-days treatment cycle up to disease progression, development of unacceptable toxicity, lost to follow up, withdrawal of consent, participant's choice, pregnancy, or study termination by sponsor (approximately 27 months).

Overall Study

Digestive System Diseases

Skin and Connective Tissue Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

Ear, Nose, and Throat Diseases

Colorectal Neoplasms

Melanoma

Carcinoma, Non-Small-Cell Lung

Glioma

Thyroid Cancer, Papillary

Ovarian Neoplasms

Multiple Myeloma

Neoplasms, Plasma Cell

Hematologic Neoplasms

Erdheim-Chester Disease

Laryngeal Neoplasms

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Gonadal Disorders

Histiocytosis

Histiocytosis, Non-Langerhans-Cell

Lymphatic Diseases

Otorhinolaryngologic Neoplasms

Laryngeal Diseases

Otorhinolaryngologic Diseases

Adenocarcinoma

Adenocarcinoma, Papillary

Ovarian Cancer

Lipogranulomatosis

Non-Langerhans-Cell Histiocytosis

Vemurafenib

This vemurafenib and cobimetinib appendix is for BRAF V600 mutation-positive malignancies occurring in adults.

Participants will receive vemurafenib at a dose of 960 mg orally on a twice daily schedule throughout a 28-day cycle.

Participants will receive cobimetinib at a dose of 60 mg (3 tablets of 20 mg) to be taken orally, once daily for 21 consecutive days (days 1 to 21 in each 28-day cycle); followed by a 7-day break.

Cobimetinib

Aida Sarmiento Castro

Vicky Coyle, Prof

Gary Middleton, Prof

Antony Ng, Dr

Bristi Basu, Dr

Robert Jones, Dr

Stefan Symeonides, Dr

Patricia Roxburgh, Dr

Martin Elliott, Dr

Anne Thomas, Dr

Martin Foster, Prof

James Spicer, Dr

Matthew Krebs, Prof

Alastair Greystoke, Dr

Sarah Pratap, Dr

Sarah Danson, Dr

Juliet Gray, Prof

Dan Palmer, Dr

Matthew Krebs

This clinical trial is looking at a combination of drugs called vemurafenib and cobimetinib. Vemurafenib is approved as standard of care for adult patients with unresectable or metastatic melanoma. Cobimetinib is approved as standard of care in combination with vemurafenib for the treatment of adult patients with unresectable or metastatic melanoma.

Cobimetinib and vemurafenib work in patients with these types of cancers which have certain changes in the cancer cells called BRAF V600 mutation-positive.

Investigators now wish to find out if it will be useful in treating patients with other cancer types which are also BRAF V600 mutation-positive. If the results are positive, the study team will work with the NHS and the Cancer Drugs Fund to see if these drugs can be routinely accessed for patients in the future.

This trial is part of a trial programme called DETERMINE. The programme will also look at other anti-cancer drugs in the same way, through matching the drug to rare cancer types or ones with specific mutations.

DETERMINE Treatment arm 05 (vemurafenib and Cobimetinib) aims to evaluate the efficacy of vemurafenib and cobimetinib in adult patients with rare\* cancers with BRAF V600 mutations or in common cancers where BRAFV600 mutations and considered to be infrequent.

\*Rare is defined generally as incidence less than 6 cases in 100,000 patients or common cancers with rare alterations.

This treatment arm has a target sample size of 30 evaluable patients. Sub-cohorts may be defined and further expanded where promising activity is identified to a target of 30 evaluable patients each.

The ultimate aim is to translate positive clinical findings to the NHS (Cancer Drugs Fund) to provide new treatment options for rare adult cancers.

OUTLINE:

Pre-screening: The Molecular Tumour Board makes a treatment recommendation for the participant based on molecularly-defined cohorts.

Screening: Consenting participants undergo biopsy and collection of blood samples for research purposes.

Treatment: Participants will receive vemurafenib and cobimetinib until disease progression, unacceptable toxicity or withdrawal of consent. Participants will also undergo collection of blood samples at various intervals while receiving treatment and at EoT.

After completion of study treatment, patients are followed up every 3 months for 2 years.

THE DETERMINE TRIAL MASTER (SCREENING) PROTOCOL:

Please see DETERMINE Trial Master (Screening) Protocol record (NCT05722886) for information on the DETERMINE Trial Master Protocol and applicable documents.

DETERMINE Trial Treatment Arm 05: Vemurafenib in Combination With Cobimetinib in Adult Patients With BRAF Positive Cancers.

DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial): An Umbrella-Basket Platform Trial to Evaluate the Efficacy of Targeted Therapies in Rare Adult, Paediatric and Teenage/Young Adult (TYA) Cancers With Actionable Genomic Alterations, Including Common Cancers With Rare Actionable Alterations Treatment Arm 05: Vemurafenib in Combination With Cobimetinib in Adult Patients With BRAF Positive Cancers.

Individual de-identified patient data will be shared with researchers whose proposed use of the data is approved by a review committee of the Sponsor.

An OR is defined as the confirmed occurrence of either a Complete Response (CR) or Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 criteria (or immune related (ir)-RECIST or standard imaging criteria for specific disease e.g. Response Evaluation in Neuro Oncology criteria (RANO)). In patients with leukaemia, OR will be defined as the occurrence of CR , CRi (CR incomplete neutrophil recovery) or CRp (CR with incomplete platelet recovery). The trial will report the proportion of patients with an OR and 95% credible interval.

DCB is defined as the absence of disease progression for at least 24 weeks from the start of trial treatment according to RECIST Version 1.1 criteria (or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria). Alternative definitions of DCB based on different time points may be pre-specified for particular sub-cohorts if 24 weeks is not clinically relevant. The trial will report the proportion of patients with a DCB and 95% credible interval.

Duration of response, is defined as the time from the date of the first confirmed CR or PR according to RECIST 1.1 or ir-RECIST or standard imaging criteria for specific disease e.g. RANO criteria to the date of disease progression. The trial will report the median DR and 95% credible interval.

PCSD is defined as the greatest decrease or least increase in the sum of target lesion diameters (RECIST) or index lesion diameters (irRECIST) as a percentage compared to the baseline measurement. The trial will report the mean PCSD and 95% credible interval.

TTD is defined as the time from date of starting trial treatment to date of discontinuing trial treatment, in days estimated by the median of the posterior inverse gamma probability distribution. The trial will report the median TTD and 95% credible interval.

PFS is defined as the time from date of starting trial treatment to date of progression or date of death without a previous progression recorded estimated by the median of the posterior inverse gamma probability distribution.

TTP is defined as the time from date of starting trial treatment to date of progression or date of death without recorded progression censored rather than events. The trial will report the median TTP and 95% credible interval.

GMI is defined as the ratio of TTP with the trial protocol treatment to TTP on the most recent prior line of therapy. The trial will report the mean GMI and 95% credible interval.

OS is defined as the time from date of starting trial treatment to date of death from any cause estimated by the median of the posterior normal probability distribution.

The trial will report the number of patients who experience at least one SUSAR to vemurafenib and cobimetinib.

Number of patients who experience at least one vemurafenib and cobimetinib related Grade 3, 4 or 5 AE according to NCI CTCAE Version 5.0.

Multiple measures of QoL will be generated from patient completion of the European Organisation for Research and Treatment of Cancer QLQC30 (EORTC-QLQC30) questionnaire (30 measures). For each patient the Summary Score from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean QLQSAUC and 95% credible interval.

Two measures of QoL will be generated from patient completion of the EQ-5D-5L questionnaire. For each measure, scores based on responses from the questionnaire will be generated at each time point and the area under the curve generated by these scores over time will be calculated and standardised by the time frame. The trial will report the mean EQ5DSAUC and 95% credible interval.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase 2 Trial of Lenvatinib for the Treatment of Anaplastic Thyroid Cancer (ATC)	NCT02657369	Thyroid Carcino...	Lenvatinib 24 m...	18 Years - 99 Years	Eisai Inc.
DETERMINE Trial Treatment Arm 05: Vemurafenib in Combination With Cobimetinib in Adult Patients With BRAF Positive Cancers.	NCT05768178	Solid Tumor Haematological ... Melanoma Thyroid Cancer,... Ovarian Neoplas... Colorectal Neop... Laryngeal Neopl... Carcinoma, Non-... Glioma Multiple Myelom... Erdheim-Chester... Thyroid Carcino...	Vemurafenib Cobimetinib	18 Years -	Cancer Research UK

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