Study of two different doses of cabozantinib in progressive, metastatic medullary thyroid cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Exelixis Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Nov 2015 → ongoing

Decision date (initial)

2024-12-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Exelixis, Inc. United States

External identifiers

EU CT number

2024-516480-90-00

EudraCT number

2013-003402-40

WHO UTN

U1111-1147-2723

ClinicalTrials.gov

NCT01896479

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Therapy, Pharmacodynamic, Safety

The objective of this study is to evaluate the efficacy of oral cabozantinib at a daily dose of 60 mg compared with 140 mg in subjects with progressive metastatic medullary thyroid cancer.

Conditions and MedDRA coding

Metastatic Medullary Thyroid Cancer

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

IPD has been already shared with sites

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. The subject has a histologically confirmed diagnosis of MTC.
2. 2. Availability of tumor tissue for shipment to the central laboratory according to prior determination of RET mutation status: a. For subjects lacking evidence of a RET or RAS mutation, a recent tumor tissue sample (defined as collected within 6 months prior to randomization) will be required. Tissue shall come from a progressive tumor location, preferably from the most recently progressed metastatic site if feasible. If a recent tumor sample is not available, a tumor biopsy will be obtained during screening. b. Subjects with documentation of a RET or RAS mutation found in tumor tissue will not be required to submit a recent tumor tissue sample; however, the report demonstrating the subject’s RET or RAS mutation must be reviewed and approved by the sponsor prior to subject randomization. c. For subjects with documentation of a hereditary RET mutation (ie, pathology report showing presence of a specific RET mutation identified in a blood sample), a tumor sample will not be required. Review and approval of the RET mutation report by the sponsor is required prior to randomization of the subject.
3. 3. The subject has MTC that is metastatic as determined by the investigator based upon computerized tomography (CT), magnetic resonance imaging (MRI), bone scan, PET scan, or X-ray taken within 28 days before randomization.
4. 4. The subject has disease that is measurable per RECIST 1.1 as determined by the investigator based upon CT or MRI images taken within 28 days before randomization.
5. 5. The subject has documented progressive disease (PD) on CT, MRI, PET scan, bone scan, or X-ray as determined by the investigator per RECIST 1.1 on qualifying images taken within 4 months prior to randomization as compared to previous images taken within 14 months before the qualifying images (see Section 5.5.6.2). a. PET scan can only be used to establish PD by the presence of new lesions (not to document increases in target or non-target lesions). b. Bone scan or x-ray, can only be used to establish PD by the presence of new lesions in bone (not to document increases in target or non-target lesions).
6. 6. The subject has recovered to baseline or CTCAE v4.0 (Common Terminology Criteria for Adverse Events, version 4.0) ≤ Grade 1 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy.
7. 7. The subject is ≥ 18 years old on the day of consent.
8. 8. The subject has an ECOG (Eastern Cooperative Oncology Group) status ≤ 1 at screening
9. 9. The subject has adequate organ and marrow function, based upon the following laboratory criteria from assessments performed within 28 days before randomization a. Absolute neutrophil count (ANC) ≥ 1500/mm3 b. Platelets ≥ 100,000/mm3 c. Hemoglobin ≥ 9 g/dL d. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). For subjects with known Gilbert’s disease, total bilirubin ≤ 3.0 mg/dL. e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 x ULN f. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min (using the Cockcroft-Gault equation: CrCl (mL/min) = (140 – age) x wt (kg) / (serum creatinine [mg/dL] x 72); for females multiply by 0.85 g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g h. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test results at screening ≤ 1.3 x the laboratory ULN
10. 10. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
11. 11. Sexually active fertile subjects and their partners must agree to use medically methods of contraception (defined in Appendix E) during the course of the study and for 4 months after the last dose of study treatment
12. 12. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, or ovarian suppression or other reasons.

Exclusion criteria 13

1. 1. The subject has previously received cabozantinib.
2. 2. The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 28 days or five halflives of the compound or active metabolites, whichever is shorter before randomization or at any time after the date of the qualifying images used to document PD for eligibility
3. 3. The subject has received prior systemic anti-tumor therapy (eg, chemotherapy, biologic modifiers, or anti-angiogenic therapy) within 28 days of randomization (42 days [6 weeks] for nitrosoureas or/ mitomycin C) or at any time after the date of the qualifying images used to document PD for eligibility
4. 4. The subject has received any other type of investigational agent within 28 days before randomization or at any time after the date of the qualifying images used to document PD for eligibility
5. 5. The subject has received radiation therapy within 28 days (14 days for radiation for bone metastases) or radionuclide treatment (eg, I-131 or Y-90) within 42 days (6 weeks) of randomization. Subject is ineligible if there are any clinically relevant ongoing complications from prior radiation therapy
6. 6. The subject has untreated and/or active (progressing or requiring anticonvulsants or corticosteroids for symptomatic control) central nervous system (CNS) metastasis. Must have completed radiation therapy ≥ 28 days prior to randomization and stable without corticosteroids or anti-convulsant treatment for ≥ 10 days
7. 7. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (< 1 mg/day), and low dose low molecular weight heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before randomization, and who have had no complications from a thromboembolic event or the anticoagulation regimen.
8. 8. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: a. Cardiovascular disorders including i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other ischemic event within 6 months before randomization iv. Thromboembolic event within 3 months before randomization. b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization, Note: Complete healing must be confirmed prior to randomization, including radiographic evidence of complete resolution of abdominal abscess c. Major surgery (eg, open surgery of the chest or abdominal cavity, surgery involving the viscera or removal of a large amount of tissue, removal or biopsy of brain metastasis) within 2 months before randomization. Complete healing from major surgery must have occurred 1 month before randomization. Complete healing from minor surgery (eg, simple excision, core biopsy, tooth extraction) must have occurred at least 7 days before randomization. Subjects with clinically relevant complications from prior surgery are not eligible d. Cavitating pulmonary lesion(s) or endobronchial disease e. Lesion invading a major blood vessel (eg, pulmonary artery, aorta, carotid artery, or vena cava) f. Clinically significant bleeding risk including the following within 3 months of randomization: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible external factors g. Other clinically significant disorders such as: i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)-related illness ii. Serious non-healing wound/ulcer/bone fracture iii. Malabsorption syndrome iv. Uncompensated/symptomatic hypothyroidism v. History of solid organ transplantation
9. 9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization Note: If the QTcF is >500 ms in the first ECG, a total of three ECGs should be performed. If the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard.
10. 10. The subject is unable to swallow multiple tablets or capsules
11. 11. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation
12. 12. The subject is pregnant or breastfeeding
13. 13. The subject has had a diagnosis of another malignancy within 2 years before randomization, except for superficial scan cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression free survival (PFS) per RECIST 1.1 per independent radiology review

Secondary endpoints 1

1. Objective response rate (ORR) per RECIST 1.1 per independent radiology review

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 8

Placebo 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Exelixis Inc.

Sponsor organisation

Exelixis Inc.

Address

1851 Harbor Bay Parkway

City

Alameda

Postcode

94502-3010

Country

United States

Scientific contact point

Organisation

Exelixis Inc.

Contact name

Simone Mangini

Public contact point

Organisation

Exelixis Inc.

Contact name

Simone Mangini

Third parties 2

Locations

4 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications