| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-negative gastric adenocarcinoma harboring FGFR genetic aberrations |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Substudy 1 (Cohorts 1.1 and 1.2)
To evaluate the objective response rate (ORR) of patients with HER2neg FGFRfus/amp/mt GAC treated with derazantinib monotherapy (DMT).
Substudy 1 (Cohort 1.3)
To evaluate the Progression-free survival (PFS4) of patients with HER2neg FGFRfus/amp/mt GAC treated with DMT.
Substudy 2
To determine the RP2D of derazantinib-paclitaxel-ramucirumab in combination in patients with HER2neg FGFRfus/amp/mt GAC
Substudy 3
To evaluate the ORR of patients with HER2neg FGFRfus/amp/mt GAC treated with either derazantinib, derazantinib-paclitaxel-ramucirumab, derazantinib-atezolizumab, or paclitaxel-ramucirumab |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the efficacy of the study drugs, as measured by ORR, disease control rate, duration of response, progression-free survival and overall survival.
Compare the ORR, DCR, DOR, PFS, and OS of patients treated with DMT, derazantinib-paclitaxel-ramucirumab, and derazantinib-atezolizumab each with that of patients treated with paclitaxel-ramucirumab.
Compare antitumor efficacy in patients treated with DMT to that of patients treated with derazantinib-paclitaxel-ramucirumab /derazantinib-atezolizumab as well as patients treated with derazantinib paclitaxel-ramucirumab compared to that of patients treated with paclitaxel-ramucirumab.
Assess the safety and tolerability of the study drugs.
Characterize the pharmacokinetic (PK) profile of D-MT 200 mg BID and Derazantinib in combination with paclitaxel-ramucirumab.
Characterize the PK of paclitaxel in combination with derazantinib ramucirumab.
Evaluate changes and assess the quality of life and symptom response from baseline. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| This study is an open-label, multiple-cohort, multicenter Phase 1b and randomized Phase 2 study, comprising three substudies. |
|
| E.3 | Principal inclusion criteria |
1. Informed consent signed by the patient indicating that they understand the purpose of, and procedures required for, the study, and are willing to participate in the study, prior to any study-related procedure.
2. Male or female aged ≥ 18 years.
3. Histologically-confirmed adenocarcinoma of the gastro-esophageal junction or stomach.
4. Negative HER2 status obtained from the most recent available tissue sample.
5. Inoperable recurrent, locally-advanced adenocarcinoma or progressing stage IV adenocarcinoma of the gastro-esophageal junction or stomach, and prior antitumor treatment as specified for each Substudy:
Substudy 1 : Patients with radiographically-documented disease progression after either standard first- or second-line treatment, and no approved treatment alternative.
Substudy 2: Patients with radiographically-documented disease progression after standard first-line treatment, and per Investigator assessment considered suitable to tolerate the treatment regimen.
Substudy 3: Patients with objective radiographically-documented disease progression:
- During, or within 6 months after, administration of the last cycle of adjuvant / neoadjuvant / perioperative chemotherapy (platinum plus fluoropyrimidine with or without anthracycline and/or taxane and/or irinotecan) for locally advanced disease, or
- During, or any time after, administration of the last cycle of first-line taxane-free chemotherapy (platinum plus fluoropyrimidine with or without anthracycline) for metastatic disease or locally advanced disease.
6. Eigible FGFRfus/amp/mt positive test result.
7. Measurable disease as defined by the Investigator using Response Evaluation Criteria in Solid Tumors 1.1 criteria (RECIST 1.1)
disease per RECIST 1.1 is not required for Substudy 2.
8. ECOG PS 0 or 1.
9. Adequate organ functions, as indicated by Screening visit local laboratory values
10. Men and women of childbearing potential must agree to avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 150 days after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. Receipt of prior cancer treatment within specific interval periods (see Exclusion criterion 1).
2. For patients enrolled in Substudy 1, prior treatment with FGFR inhibitors.
3. For patients enrolled in Substudy 2 and 3, prior treatment with
- Taxanes within 6 months prior to randomization
- FGFR inhibitors or pathway-targeting agents
- Anti-VEGF(R) therapeutic antibody or pathway-targeting agents.
4. For patients enrolled in Substudy 3, prior treatment with anti-programmed cell death receptor-1 (PD-1) or anti-programmed death ligand-1 (PD-L1) therapeutic antibody or pathway-targeting agents.
5. Concurrent evidence of clinically significant corneal or retinal disorder likely to increase the risk of eye toxicity, including but not limited to bullous/band keratopathy, keratoconjunctivitis (unless keratoconjunctivitis sicca), corneal abrasion (unless related to trauma), inflammation/ulceration, confirmed by ophthalmological examination.
6. History of clinically significant cardiac disorders: New York Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of study drug; any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months of the first dose of study drug, concurrent and clinically significant abnormalities on electrocardiogram [ECG] at Screening, including a QT interval corrected by Fridericia’s formula [QTcF]1 > 450 ms for males or > 460 ms for females (mean values from triplicate ECGs).
7. Any unresolved clinically-significant Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2 toxicity. (Exception: patients with alopecia, Grade ≤2 platinum-therapy related neuropathy, or Grade ≤ 2 anemia from previous anti-tumor treatment and/or from medical/surgical procedures/interventions, may be enrolled).
8. Known central nervous system (CNS) metastases.
...
18. Pregnant or breast feeding.
Applicable to patients considered for enrollment in Substudy 2 or 3:
19. Concurrent uncontrolled or active infection with human immunodeficiency virus (HIV, known HIV 1/2 antibodies positive)
20. Active hepatitis or chronic hepatitis B without current antiviral therapy and an HBV DNA ≥ 100 IU/mL.
21. Active hepatitis C.
22. Active tuberculosis
23. Lack of recovery from major surgery after 4 weeks, or major elective surgery is planned during the foreseeable duration of the patient's participation in the study, or placement of a central venous access device within 7 days prior to randomization.
24. Uncontrolled arterial hypertension, with a systolic blood pressure ≥ 150 mm Hg or a diastolic blood pressure ≥ 90 mm Hg despite standard medical management.
25. History of gastrointestinal perforation and/or fistulae within 6 months prior to study entry.
26. History of clinically relevant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 3 months prior to study entry.
27. History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered ‘significant’) during the 3 months prior to randomization.
28. The patient is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin, or similar agents.
29. The patient is receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs, e.g. indomethacin, ibuprofen, naproxen, or similar agents) or other anti-platelet agents (e.g. Clopidogrel, ticlopidine, dipyridamole, anagrelide). Acetylsalicylic acid (aspirin) is permitted at doses up to 325 mg/day.
30. Child-Pugh B or C liver cirrhosis, or a history of hepatic encephalopathy, hepatorenal syndrome, or clinically-meaningful ascites related to cirrhosis.
31. The patient has a serious or non-healing wound, ulcer, or bone fracture within 28 days prior to randomization. Applicable only to patients considered for enrollment in Substudy 3:
32. Administration of a live, attenuated vaccine within 30 days prior to randomization.
33. Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to first dose of study drug or anticipated requirement for systemic immunosuppressive medications during the study; inhaled, intranasal, intraocular, topical, and intra-articular joint injections are allowed.
34. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently).
35. History of allogeneic stem cell or solid organ transplantation.
...
38.History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on Screening chest computed tomography (CT) scan |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Substudy 1, Cohorts 1.1 and 1.2:
ORR, as measured by the proportion of patients with confirmed complete response (CR) or partial response (PR) by blinded independent central review (BICR) per RECIST 1.1. To determine the study population for Substudy 3, the outcomes of patients with HER2neg FGFRfus/amp/mt GAC treated with derazantinib in Substudy 1 are to be analyzed per cohort.
Substudy 1,Cohort 1.3:
PFS4, as measured by the proportion of patients alive and free of disease progression by survival status and BICR per RECIST 1.1 after approximately 4 months of study treatment.
Substudy 2:
The recommended Phase 2 dose (RP2D) of derazantinib-paclitaxel-ramucirumab in combination, estimated from safety and tolerability according to the aggregate of dose-limiting toxicity (DLT) criteria and adverse event (AE) data, and considering further PK and efficacy data of the combination. If the triple combination is not tolerated at the lowest dose level, the combination of derazantinib and paclitaxel will be explored instead. In a joint decision, the IDMC, Investigators, and the Sponsor will determine the RP2D.
Substudy 3:
ORR, as measured by the proportion of patients with confirmed CR or PR by BICR. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For all cohorts in Substudies 1 and 3, efficacy will be evaluated on C3D1 ±7 days, then every 8 weeks (±7 days) for the first 6 months, and every 12 weeks (±7 days) thereafter.
In Substudy 2, DLT interval is defined as the first 28-day interval of study treatment. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints for Substudy 1:
- PFS of patients treated with derazantinib, as measured from patient enrollment to PD date by BICR
- ORR, as measured by the proportion of patients with confirmed CR or PR by BICR for Cohort 1.3
- Disease control rate (DCR), as measured by the proportion of patients with confirmed CR, PR or stable disease (SD) by BICR
- Duration of response (DOR), as calculated from the first date of documented tumor response to disease progression by BICR (or death if no documentation of PD is obtained)
- OS, as measured from patient enrollment to time of death
- Safety and tolerability of study drugs, as measured by the frequency and severity of AEs (graded by CTCAE version 5.0), clinical laboratory parameters, vital signs, ECOG PS, physical examinations (including eye examinations), and ECG parameters over time
- DLT in the first ten patients in Substudy 1.3
- Derazantinib (and, if applicable, derazantinib metabolites) plasma concentrations, Cmax, tmax, AUC0–12, AUC0–24, AUC last assessed by measurements in blood samples
Secondary endpoints for Substudy 2:
- ORR, as measured by the proportion of patients with confirmed CR or PR by BICR
- DCR, as measured by the proportion of patients with confirmed CR, PR or SD by BICR
- DOR, as calculated from the first date of documented tumor response to disease progression by BICR (or death if no documentation of PD is obtained)
- PFS of patients treated with derazantinib-paclitaxel-ramucirumab, as measured from patient enrollment to PD date by BICR
- OS, as measured from patient enrollment to time of death
- Safety and tolerability of study drugs, as measured by the frequency and severity of AEs (graded by CTCAE version 5.0), clinical laboratory parameters, vital signs, ECOG PS, physical examinations (including eye examinations), and ECG parameters over time
- Derazantinib (and – if applicable –derazantinib metabolites) plasma concentrations, Cmax, tmax, AUC0-24, AUClast, assessed by measurements in blood samples
- Paclitaxel plasma concentrations, Cmax, tmax, AUC0-24, AUClast, t1/2, AUCinf, T > 0.05 assessed by measurements in blood samples.
Secondary endpoints for Substudy 3:
- ORR of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or derazantinib-atezolizumab, as measured by the proportion of patients with confirmed CR or PR by BICR, and for each treatment compared to that of paclitaxelramucirumab.
- PFS of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or derazantinib-atezolizumab, as measured from randomization to PD date by BICR, and for each treatment compared to that of paclitaxel-ramucirumab.
- DCR of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or derazantinib-atezolizumab, as measured by the proportion of patients with confirmed CR, PR or stable disease (SD)1 by BICR, and for each treatment compared to that of
paclitaxel-ramucirumab.
- DOR of patients treated with derazantinib, derazantinib-paclitaxelramucirumab, or derazantinib-atezolizumab, as calculated from the first date of documented tumor response to disease progression by BICR (or death if no documentation of PD is obtained), and for each treatment compared to that of paclitaxel-ramucirumab.
- OS of patients treated with derazantinib, derazantinib-paclitaxel-ramucirumab, or derazantinib-atezolizumab, as measured from patient enrollment to time of death, and for each treatment compared to that of paclitaxel-ramucirumab. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All patients will undergo assessments for clinical safety on D1 and D15 of Cycle 1 and on D1 (+3 days) of every subsequent treatment cycle, with paclitaxel-ramucirumab-treated patients also undergoing these assessments at the treatment administration visits on D8 (+3 days) and D15 (+3 days) of every treatment cycle.
Efficacy will be evaluated on C3D1 ±7 days, then every 8 weeks (±7 days) for the first 6 months, and every 12 weeks (±7 days) thereafter (see Section 5.3.3.2).
AEs will be assessed continuously and at every study visit.
HR-QoL questionnaires will be completed by the patient before the patient sees the physician (i.e., at the start of the visit) on D1 of every cycle |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Open-label, multiple-cohort, multicenter Phase 1b |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Open-label, multiple-cohort, multicenter Phase 1b and randomized Phase 2 study |
|
| 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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Brazil |
| Chile |
| Korea, Republic of |
| United States |
| France |
| Poland |
| Spain |
| Germany |
| Italy |
| Belgium |
| Russian Federation |
| Turkey |
| 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
|
| The study ends when the last patient completes the last study-related phone-call or visit, discontinues from the study or is lost to follow-up (i.e. the patient is unable to be contacted by the investigator). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 8 |
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