Derazantinib Alone or in Combination With Paclitaxel, Ramucirumab or Atezolizumab in Gastric Adenocarcinoma

The purpose of this study was to evaluate the efficacy of derazantinib monotherapy or derazantinib in combination with paclitaxel and ramucirumab in patients with gastric adenocarcinoma (GAC) i.e. with human epidermal growth factor receptor 2 (HER2)-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring fibroblast growth factor receptor 2 (FGFR2) genetic aberrations (GA).

The study comprised two open-label substudies in patients with HER2-negative adenocarcinoma of the stomach or gastro-esophageal junction harboring FGFR2 gene translocations, FGFR2 gene amplifications, or FGFR1-3 mutations.

In Substudy 1, GAC patients with specified FGFR GAs, after either first- or second-line treatment, and no approved treatment alternative were treated with derazantinib 300 mg once daily or 200 mg twice daily, with the aim of evaluating the safety, tolerability, and efficacy of derazantinib monotherapy in this patient population.

In Substudy 2, GAC patients with specified FGFR GAs after standard first-line treatment, were treated with a derazantinib-paclitaxel-ramucirumab combination with the aim of evaluating the safety, tolerability, and efficacy of the combination therapy and determining the recommended phase 2 dose (RP2D).

The study originally planned to include three substudies but was prematurely terminated for administrative reasons before the third substudy (including combination therapy with derazantinib plus atezolizumab) was initiated.

Eligibility Criteria:
Main inclusion criteria

Patients meeting all of the inclusion criteria at screening were eligible for enrollment in the study, including:

1. Histologically-confirmed adenocarcinoma of the gastro-esophageal junction or stomach.
2. Negative HER2 status obtained from the most recent available tissue sample.
3. Inoperable recurrent, locally advanced adenocarcinoma or progressing stage IV adenocarcinoma of the gastro-esophageal junction or stomach, and prior anti-tumor treatment as specified for each Substudy. Patients were required to be staged as inoperable at the time of screening in order to avoid interference of any potentially planned surgery with RECIST requirements during the study:

   Substudy 1: Patients with radiographically documented disease progression after either standard first- or second-line treatment, and no approved and/or tolerable 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.
4. Eligible FGFRfus/amp/mt positive test result. For Substudy 1 Cohort 1.1, FGFR2fus/amp; for Cohort 1.2, FGFR1-3mt; for Cohort 1.3, FGFRfus/amp/mt. For Substudy 2, FGFRfus/amp/mt.
5. Measurable disease as defined by the Investigator using RECIST 1.1 criteria
6. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
7. Adequate organ functions as indicated by Screening visit laboratory values.

Main exclusion criteria

Patients meeting any of the following exclusion criteria at screening were not eligible to be enrolled in the study:

* Receipt of prior cancer treatment within specific interval periods.
* For patients enrolled in Substudy 1, prior treatment with FGFR inhibitors.
* For patients enrolled in Substudy 2, 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
* 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.
* History of clinically significant cardiac disorders, including myocardial infarction, or New York Heart Association Class II to IV congestive heart failure, within 6 months of the first dose of study drug, and/or 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, and/or concurrent and clinically significant abnormalities on ECG at Screening, including QTcF \> 450 ms for males or \> 460 ms for females (mean values from triplicate ECGs).
* Any unresolved (at the time of Screening) clinically significant CTCAE Grade ≥ 2 toxicity (except for alopecia, Grade ≤ 2 platinum-therapy related neuropathy, or Grade ≤ 2 anemia from previous anti-tumor treatment and/or from medical/surgical procedures/interventions).
* Known central nervous system metastases.
* Severe bacterial, fungal, viral and/or parasitic infections on therapeutic oral or IV medication at the time of first dose of study drug administration.
* Significant gastrointestinal disorders that could interfere with the absorption, metabolism, or excretion of derazantinib.
* History of additional malignancy that was progressing or required active treatment.