E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Advanced Gastrointestinal Stromal Tumors |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with Advanced Gastrointestinal Stromal Tumors |
|
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 | 10051066 |
E.1.2 | Term | Gastrointestinal stromal tumour |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy (progression-free survival [PFS]) of DCC-2618 by independent radiologic review in patients with advanced gastrointestinal stromal tumors (GIST) who have previously received first-line therapy with imatinib |
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E.2.2 | Secondary objectives of the trial |
• To assess objective response rate (ORR) by independent radiologic review using modified RECIST (mRECIST) criteria
• To assess Overall Survival (OS) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients ≥ 18 years of age at the time of informed consent.
2. Histologic diagnosis of GIST and must be able to provide an archival tumor tissue sample, otherwise, a fresh biopsy is required.
3. Molecular pathology report with mutational status of KIT/PDGFRA must be available. Mutation status must be identified using a tissue based PCR/sequencing assay. Molecular pathology report with
mutation status of KIT/PDGFRA must be provided to the Sponsor for review prior to randomization. If the molecular pathology report is not available or insufficient, an archival tumor tissue sample or fresh
biopsy is required for mutation status confirmation by the central laboratory prior to randomization.
4. Patients must have progressed on imatinib or have documented intolerance to imatinib. Imatinib treatment must have been discontinued 10 days prior to the first dose of study drug. All prior
imatinib treatment will count as one line of therapy (e.g. adjuvant imatinib and dose escalation of imatinib).
5. Eastern Cooperative Oncology Group (ECOG) PS of ≤ 2 at screening.
6. Female patients of childbearing potential must have a negative serum beta-human chorionic gonadotrophin (β-hCG) pregnancy test at screening and negative pregnancy test at Cycle 1 Day 1 prior to the first dose of study drug.
7. Patients of reproductive potential must agree to follow contraception requirements outlined in the Protocol.
8. Patients must have at least 1 measurable lesion according to mRECIST Version 1.1 (non-nodal lesions must be ≥ 1.0 cm in the long axis or ≥
double the slice thickness in the long axis) within 21 days prior to the first dose of study drug.
9. Adequate organ function and bone marrow reserve as indicated by the central laboratory assessments performed at screening:
a. Absolute Neutrophil Count (ANC) ≥ 1000/μL
b. Hemoglobin ≥ 8 g/dL
c. Platelet count ≥ 75,000/μL
d. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN)
e. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x
ULN (≤ 5x ULN in the presence of hepatic metastases)
f. Creatinine clearance ≥ 50 ml/min based on Cockcroft Gault estimation
g. Prothrombin time (PT), international normalized ratio (INR) and
partial thromboplastin time (PTT) ≤ 1.5 x ULN. Patients on a stable
regimen of anticoagulant therapy for at least one month
prior to the first dose of study drug may have PT/INR measurements >
1.5 x ULN if, in the opinion of the Investigator, the patient is suitable for
the study. An adequate rationale must be provided to the Sponsor prior
to randomization.
10. Resolution of all toxicities from prior therapy to ≤ Grade 1 (or patient
baseline) within 1 week prior to the first dose of study drug (excluding
alopecia and ≤ Grade 3 clinically asymptomatic lipase, amylase, and
creatine phosphokinase (CPK) laboratory abnormalities).
11. The patient is capable of understanding and complying with the
protocol and the patient has signed the informed consent document.
Signed informed consent form (ICF) must be obtained before any study specific
procedures are performed and the patient must agree to not
participate in any other interventional clinical trial while on treatment in
this clinical trial. Participation in a noninterventional study (including
observational studies) is permitted. |
|
E.4 | Principal exclusion criteria |
1. Treatment with any other line of therapy in addition to imatinib for
advanced GIST. Imatinib-containing combination therapy in the first-line
setting is not allowed.
2. Patients with a prior or concurrent malignancy whose natural history
or treatment have the potential to interfere with the safety or efficacy
assessment of this clinical trial are not eligible. For
example, patients receiving adjuvant cancer treatment are not eligible if
those medications are potentially active against GIST or excluded per
protocol.
NOTE: Patients with a history of breast cancer, requiring continued
hormonal treatment (e.g. anti-estrogen or an aromatase inhibitor) may
continue treatment. Patients with a history of prostate cancer, requiring
continued support with luteinizing hormone-releasing hormone (LHRH)
agonists, with or without androgens, may continue treatment.
NOTE: Patients may not be part of an ongoing or have prior participation
in an investigational drug study within 30 days of screening.
3. Patient has known active central nervous system metastases.
4. New York Heart Association class II-IV heart disease, myocardial
infarction within 6 months of cycle 1 day 1, active ischemia or any other
uncontrolled cardiac condition such as angina pectoris, clinically
significant cardiac arrhythmia requiring therapy, uncontrolled
hypertension or congestive heart failure.
5. Left ventricular ejection fraction (LVEF) < 50% at screening.
6. Arterial thrombotic or embolic events such as cerebrovascular
accident (including ischemic attacks) or hemoptysis within 6 months
before the first dose of study drug.
7. Venous thrombotic events (e.g. deep vein thrombosis) or pulmonary
arterial events (e.g. pulmonary embolism) within 1 month before the
first dose of study drug. Patients on stable anticoagulation therapy for at
least one month are eligible.
8. 12-lead electrocardiogram (ECG) demonstrating QT interval corrected
(QTc) by Fridericia's formula > 450 ms in males or > 470 ms in females
at screening or history of long QTc syndrome.
9. Use of strong or moderate inhibitors or inducers of cytochrome P450
(CYP) 3A4, including certain herbal medications (e.g. St. John's Wort)
within 14 days or 5 x the half-life (whichever is longer) prior to the first
dose of study drug, and consumption of grapefruit or grapefruit juice
within 14 days prior to the first dose of study drug. Please refer to the
Indiana University Department of Medicine website
(http://medicine.iupui.edu/clinpharm/ddis/maintable/) for guidance on
medications that inhibit/induce CYP3A4 enzymes. See Section 5.12.3.3
in the Protocol.
10. Use of known substrates or inhibitors of BCRP transporters within 14
days or 5 x the half-life (whichever is longer) prior to the first dose of
study drug. Please refer to the US Food and Drug Administration's (FDA)
website for inhibitors and substrates
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/Developme
ntResources/DrugInteractionsLabeling/ucm093664.htm). See Section
5.12.3.3.
11. Major surgeries (e.g. abdominal laparotomy) within 4 weeks of the
first dose of study drug. All major surgical wounds must be healed and
free of infection or dehiscence before the first dose of study drug.
12. Any other clinically significant comorbidities, such as uncontrolled
pulmonary disease, active infection, or any other condition, which in the
judgment of the Investigator, could compromise compliance with the
protocol, interfere with interpretation of the study results, or predispose
the patient to safety risks.
13. Known human immunodeficiency virus or hepatitis C infection only if
the patient is taking medications that are excluded per protocol (Section
5.12.3.2), active hepatitis B, or active hepatitis C infection.
14. If female, the patient is pregnant or lactating.
15. Known allergy or hypersensitivity to any component of the study
drug. Patients with history of Stevens-Johnson syndrome on a prior
tyrosine kinase inhibitor (TKI) are excluded.
16. Gastrointestinal abnormalities including, but not limited to:
a. inability to take oral medication
b. malabsorption syndromes
c. requirement for intravenous (IV) alimentation
17. Any active bleeding excluding hemorrhoidal or gum bleeding. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy
PFS based on independent radiologic review using modified RECIST (mRECIST) (Appendix 17.1). mRECIST criteria includes:
• No lymph nodes chosen as target lesions; enlarged lymph nodes followed as non-target lesions;
• No bone lesions chosen as target lesions;
• PET not acceptable for radiological evaluation;
• A progressively growing new tumor nodule within a pre-existing tumor mass must meet the following criteria to be considered as unequivocal evidence of progression according to the modification of RECIST Version 1.1: (a) the lesion is at least 2 cm in size and definitively a new active GIST lesion (e.g. enhancing with contrast or other criteria to rule out artefact); or (b) the lesion has to be expanding on at least 2 sequential imaging studies. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint of PFS (reported in weeks) is defined as the interval between the date of randomization and the earliest documented
evidence of disease progression based on the independent radiologic review, or death due to any cause. Patients who undergo surgical
resection of target or non-target lesions, who have received other anticancer treatments, or patients who do not have a documented date of progression or death due to any cause will be censored at the date of the last assessment. |
|
E.5.2 | Secondary end point(s) |
Efficacy
• ORR (confirmed CR + confirmed PR) based on independent radiologic review using mRECIST criteria
• OS
The primary and secondary endpoints will be analyzed for both the KIT
Exon 11 (Exon 11 ITT) and the All Patients (AP ITT) population.
Safety
Safety endpoints that will be evaluated include treatment-emergent adverse events (TEAEs), AESIs, SAEs, dose reduction or discontinuation of study drug due to toxicity; and changes from baseline in ECOG PS, vital signs, ECGs, LVEF, dermatologic examinations, and clinical laboratory parameters.
Pharmacokinetics
• Correlation of PK exposure with efficacy/safety
• Population-based PK parameters
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Objective response rate: to be assigned a status of a CR or PR, changes in tumor measurements must be confirmed by repeat assessments that must be performed at least 4 weeks after the criteria for response are first met. Patients with unknown or missing response will be treated as non responders, that is, they will be included in the denominator when calculating the proportion. Time to confirmed response (CR or PR) (reported in weeks) is defined as the interval between the date of first dose of study medication and the earliest date of first documented confirmed CR or confirmed PR. Patients who do not have a confirmed PR or CR will be censored at the date of the last adequate assessment. |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 |
Argentina |
Australia |
Belgium |
Canada |
Chile |
Czechia |
France |
Germany |
Hungary |
Israel |
Italy |
Korea, Democratic People's Republic of |
Netherlands |
Norway |
Poland |
Singapore |
Spain |
Sweden |
Switzerland |
Taiwan |
United Kingdom |
United States |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |