| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic gastrointestinal stromal tumor (GIST) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Tumor of the gastrointestinal tract |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062427 |
| E.1.2 | Term | Gastrointestinal stromal tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 compare the treatment effect of crenolanib with that of placebo on prolonging progression-free survival (PFS) in subjects with advanced or metastatic GIST with a PDGFRA D842V mutation. |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the treatment effect of crenolanib with that of placebo on overall survival (OS) and objective response rate (ORR). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically-confirmed advanced or metastatic GIST with a D842V mutation in the PDGFRA gene as determined by central laboratory testing
2. Measurable disease as per modified RECIST 1.1
- A lesion in an area that was previously treated with local therapy (e.g. radiation, surgery, or cryotherapy) can be considered measurable disease as long as there is objective evidence of progression of the lesion prior to randomization
3. Disease progression per modified RECIST 1.1 within 6 months of randomization
4. Subjects (male or female) ≥ 18 years of age
5. Adequate bone marrow function, defined as:
- ANC of ≥ 1000 /µL
- Platelet count of ≥ 75 x 10^9/L
6. Adequate hepatic function, defined as:
- Serum total bilirubin within normal limits
- Serum aspartate aminotransferase (AST) ≤ 2.0 x upper limit of normal (ULN)
- Serum alanine aminotransferase (ALT) ≤ 2.0 x ULN
7. Adequate renal function, defined as:
- Serum creatinine ≤ 1.5 x ULN or
- Creatinine clearance estimate of ≥ 50 mL/min (as calculated according to Cokcroft-Gault formula or MDRD formula for subjects > 65 years).
8. Female subjects with reproductive potential must have negative serum or urine pregnancy test
Female subjects who meet at least one of the following criteria are defined as women of non-reproductive potential:
- ≥50 years old and naturally amenorrheic for ≥ 1 year
- Permanent premature ovarian failure confirmed by a gynecologist
- Previous bilateral salpingo-oophorectomy
- XY genotype, Turner’s syndrome, or uterine agenesis
9. Prior treatment with imatinib, sunitinib, regorafenib, dasatinib and/or nilotinib is allowed. Recovered from prior treatment-related toxicity to Grade ≤ 2 per CTCAE v4.03 or the subject's baseline preceding the prior treatment.
10. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
11. Adequate contraception:
- Female subjects with reproductive potential in combination with their partner must use 2 forms of highly effective methods of contraception during study treatment and for at least 30 days after ending treatment
- Male subjects in combination with their partner must use 2 forms of highly effective methods of contraception during study treatment and for at least 90 days after ending treatment
12. Written informed consent before any study-specific procedure is performed |
|
| E.4 | Principal exclusion criteria |
1. Severe liver disease (e.g. cirrhosis, non-alcoholic steatohepatitis, sclerosing cholangitis)
2. Known, active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
- Active infection with HBV is defined as:
o Acute hepatitis B (diagnosed < 6 months prior to randomization), or
o Serologic test positive for HBV surface antigen (HBsAg) positive, or
o Serologic test positive for immunoglobulin (IgM) to HBV core antigen (IgM anti-HBc)
- Active infection with HCV is defined as:
o Acute hepatitis C (diagnosed < 6 months prior to randomization), or
o Positive for HCV ribonucleic acid (RNA)
Subjects with history of positive anti-HCV screening test (e.g. enzyme immune-assay [EIA], chemiluminescence immunoassay [CIA], or recombinant immunoblot assay [RIA]) should be tested for HCV RNA
3. History of other malignancy within the past 3 years, except:
- Malignancy treated with curative intent and with no evidence of disease and considered to be at low risk of recurrence by the treating physician
- Adequately treated non-melanoma skin cancer or lentigo maligna with no evidence of disease
- Adequately treated cervical carcinoma in situ with no evidence of disease
- Adequately treated breast ductal carcinoma in situ with no evidence of disease
- Adequately treated prostatic intraepithelial neoplasia with no evidence of disease
- Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ with no evidence of disease
4. Any disorder that compromises the subject’s ability to give written informed consent and/or to comply with study procedures
5. Any severe and/or uncontrolled medical or psychiatric conditions that in the opinion of the investigator, may prevent the subject from completing the study, interfere with the evaluation of safety and/or efficacy, or interfere with the interpretation of the study results
6. Female subject who is pregnant or breastfeeding, or planning to become pregnant within 30 days after ending treatment
7. Systemic anti-cancer treatment (e.g. chemotherapy, tyrosine kinase inhibitors, immunotherapy, or investigational agents) or investigational device within 3 weeks or 5 half-lives (if the drug’s halflife in subject is known) prior to randomization, whichever is shorter
8. Prior administration of crenolanib |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Overall survival
- Objective response rate (based on modified RECIST 1.1) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| France |
| Germany |
| Italy |
| Norway |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
