Study of Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04940052
• Collaborator: (none)
• Enrollment: 150
• Locations: 31
• Arms: 2
• Anticipated Duration (Months): 59.5
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

150 adults patients with locally advanced or metastatic BRAFV600E mutation-positive, differentiated thyroid carcinoma who are refractory to radioactive iodine and have progressed following prior VEGFR targeted therapy will enter in the trial. Patients will be randomized in a 2:1 ratio to either dabrafenib plus trametinib or placebo. Patients will be stratified by number of prior VEGFR targeted therapy (1versus2) and prior lenvatinib treatment (yes versus no)

Condition or Disease	Intervention/Treatment	Phase
Differentiated Thyroid Cancer	Drug: Dabrafenib; Drug: Trametinib; Drug: Trametinib placebo; Drug: Dabrafenib placebo	Phase 3

Detailed Description

This is a global, multicenter, randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy and safety of dabrafenib plus trametinib in adult patients with locally advanced or metastatic BRAFV600E mutation-positive, differentiated thyroid cancer who are refractory to radioactive iodine and have progressed following prior VEGFR targeted therapy. After eligibility assessment, approximately 150 patients will be randomized in a 2:1 ratio to either dabrafenib plus trametinib or placebo. Patients will receive dabrafenib in combination with trametinib or placebo until disease progression as per RECIST 1.1 as determined by investigator and confirmed by BIRC or loss of clinical benefit as determined by investigator, death, unacceptable toxicity, pregnancy, withdrawal of consent, lost to follow-up or early termination of the study by the sponsor. Patients randomized in the placebo arm and for whom progression as per RECIST 1.1 is confirmed by blinded independent review committee and who meet the criteria will be given the option to cross over to the open label combination drug dabrafenib plus trametinib

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Phase III Study to Evaluate the Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer (DTC)
• Actual Study Start Date: Nov 15, 2021
• Anticipated Primary Completion Date: Feb 19, 2024
• Anticipated Study Completion Date: Oct 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dabrafenib plus trametinib Participants will be treated with dabrafenib twice daily and trametinib once daily	Drug: Dabrafenib; Dabrafenib will be administered orally twice daily; Drug: Trametinib; Trametinib will be administered orally once daily
Placebo Comparator: Placebo dabrafenib plus placebo trametinib Participants will receive placebo dabrafenib twice daily and placebo trametinib once daily	Drug: Trametinib placebo; Trametinib will be administered orally once daily; Drug: Dabrafenib placebo; Dabrafenib placebo will be administered orally twice daily

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival [From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 2 years]

   Progression Free Survival is based on the blinded independent review committee assessment using RECIST 1.1

Secondary Outcome Measures

1. Overall Response Rate [From randomization up to approximately 2 years]

   overall response rate is defined as the proportion of patients with best overall response of complete response or partial response assessed per blinded independent review committee using RECIST 1.1 criteria

2. Overall Survival [From randomization to death assessed up to approximately 5 years]

   Overall survival is defined as the time from the date of randomization to the date of death to any cause.

3. Duration of response [Duration of response from the start date of the first documented response of complete response or partial response and the date defined as the date of the first documented progression or death due to any cause up to 2 years]

   Duration of response only applies to patients whose best overall response is complete response or partial response according to RECIST 1.1 and based on blinded independent review committee.

4. Number of participants with trametinib associated serous retinopathy ocular events [screening, week 4, week 8, week 12, week 20 and every 12 weeks after week 20, up to approximately 2 years]

   Standard ophthalmic examination will by done by an ophthalmologist and optical coherence tomography conducted at mandated visit. Analysis using optical coherence tomography data will be done to assess the incidence, type and severity of ocular events

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent must be obtained prior to performing any specific pre-screening and screening procedure

• Male or female >= 18 years of age at the time of informed consent

• Histologically or cytologically confirmed diagnosis of advanced/metastatic differentiated thyroid cancer

• Radio active iodine refractory disease

• BRAFV600E mutation positive tumor sample as per Novartis designated central laboratory result

• Has progressed on at least 1 but not more than 2 prior VEGFR targeted therapy

• Eastern Cooperative Oncology Group performance status >= 2

• At least one measurable lesion as defined by RECIST 1.1

Exclusion Criteria:

• Anaplastic or medullary carcinoma of the Tyroid

• Previous treatment with BRAF inhibitor and/or MEK inhibitor

• Concomitant RET Fusion Positive Thyroid cancer

• Receipt of any type of small molecule kinase inhibitor within 2 weeks before randomization

• Receipt of any type of cancer antibody or systemic chemotherapy within 4 weeks before randomization

• Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before randomization

• A history or current evidence/risk of retinal vein occlusion or central serous retinopathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Buenos Aires		Argentina	C1012AAR
2	Novartis Investigative Site	Calgary	Alberta	Canada	T2N 4N2
3	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 1Z2
4	Novartis Investigative Site	London	Ontario	Canada	N6A 5W9
5	Novartis Investigative Site	Fuzhou	Fujian	China	350013
6	Novartis Investigative Site	Wuhan	Hubei	China	430022
7	Novartis Investigative Site	Xuzhou	Jiangsu	China	221003
8	Novartis Investigative Site	Chengdu	Sichuan	China	610041
9	Novartis Investigative Site	Tianjin	Tianjin	China	300060
10	Novartis Investigative Site	Tianjin	Tianjin	China	300121
11	Novartis Investigative Site	Beijing		China	100036
12	Novartis Investigative Site	Beijing		China	100730
13	Novartis Investigative Site	Changsha		China	410013
14	Novartis Investigative Site	Guangzhou		China	510060
15	Novartis Investigative Site	Tianjin		China	300052
16	Novartis Investigative Site	Mumbai	Maharashtra	India	400056
17	Novartis Investigative Site	New Delhi		India	110029
18	Novartis Investigative Site	Seoul	Seocho Gu	Korea, Republic of	06591
19	Novartis Investigative Site	Seoul		Korea, Republic of	03080
20	Novartis Investigative Site	Seoul		Korea, Republic of	05505
21	Novartis Investigative Site	Kuching	Sarawak	Malaysia	93586
22	Novartis Investigative Site	Kuala Lumpur	Wilayah Persekutuan	Malaysia	50586
23	Novartis Investigative Site	Kuala Lumpur		Malaysia	59100
24	Novartis Investigative Site	Pulau Pinang		Malaysia	10990
25	Novartis Investigative Site	Tainan		Taiwan	70403
26	Novartis Investigative Site	Taipei		Taiwan	10048
27	Novartis Investigative Site	Istanbul	TUR	Turkey	34098
28	Novartis Investigative Site	Adana		Turkey	01250
29	Novartis Investigative Site	Ankara		Turkey	06100
30	Novartis Investigative Site	Ankara		Turkey	06560
31	Novartis Investigative Site	Edirne		Turkey	22030

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04940052
• Other Study ID Numbers: CDRB436J12301
• First Posted: Jun 25, 2021
• Last Update Posted: Jul 26, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Locally advanced or metastatic differentiated thyroid cancer; radio active iodine refractory; previously targeted therapy; BRAFV600E mutation; dabrafenib; trametinib
• Additional relevant MeSH terms: Thyroid Neoplasms; Thyroid Diseases; Trametinib; Dabrafenib

Study Results

No Results Posted as of Jul 26, 2022