A Study to Find a Safe and Effective Dose of BI 905711 in Patients With Advanced Gastrointestinal Cancer

A First-in-human Phase Ia/b, Open Label, Multicentre, Dose Escalation Study of BI 905711 in Patients With Advanced Gastrointestinal Cancers

Phase 1a - Explore safety and establish the maximum tolerated dose (MTD)/recommended dose levels for phase Ib expansion phase of BI 905711 based on the frequency of patients experiencing dose limiting toxicities (DLTs) during the MTD evaluation period. The MTD evaluation period is defined as the first two treatment cycles (from first dose administration until the day preceding the third dose administration or end of REP in case of discontinuation before start of Cycle 3).

Phase 1a - Explore pharmacokinetics/pharmacodynamics, and efficacy to guide the determination of a potentially effective dose range for phase Ib in the absence of MTD.

Phase 1b - Evaluate efficacy and safety of BI 905711 at a potentially effective dose range and determine the Recommended Phase 2 Dose (RP2D)

Inclusion Criteria:

- a. Phase Ia (dose escalation only)

Histologically or cytologically confirmed, advanced unresectable or metastatic gastrointestinal cancers of following histologies:

• Colorectal adenocarcinoma

• Gastric adenocarcinoma

• Esophageal adenocarcinoma

• Pancreatic adenocarcinoma

• Cholangiocarcinoma and gallbladder carcinoma

• Small intestine adenocarcinoma b. Phase Ib (expansion phase)

• Histologically or cytologically confirmed, advanced unresectable or metastatic colorectal adenocarcinoma.

  • Patient who has failed all available conventional therapies known to confer clinical benefit for their disease based on local approved standards. For patients with colorectal cancer, prior treatment with regorafenib or TAS-102 is optional.
  • Phase Ia (dose escalation) only: Patient with either measurable or non-measurable/non-evaluable disease.
  • Phase Ia (expanded cohort) and Phase Ib (expansion phase) only: At least one target lesion that can be accurately measured per RECIST v.1.1
  • Availability and willingness to provide an archived tumor tissue specimen and undergo tumor biopsy before treatment. Pre-treatment fresh tumor biopsy collections for biomarker analyses are considered optional in phase Ia and mandatory in phase Ib. Only nonsignificant risk procedures per the investigator's judgment will be used to obtain any biopsies specified in this study. In case a fresh tumor biopsy cannot be obtained due to before mentioned reasons an archived tumor tissue specimen obtained within ≤6 months of screening must be submitted. In case the patient undergoes baseline tumor biopsy, an archived tumor tissue specimen must be submitted regardless of the date of collection.
  • Adequate hepatic, renal and bone marrow functions as defined by all of the below:

• Total bilirubin ≤ 1.5 x institutional Upper Level of Normal (ULN) (≤ 3 x institutional ULN for patient with Gilbert's syndrome)

• ALT and AST ≤2.5 x institutional ULN (≤5 x institutional ULN for patients with known liver metastases)

• Serum creatinine ≤1.5x institutional ULN. If creatinine is > 1.5 x ULN, patient is eligible if concurrent creatinine clearance ≥ 50 ml/min (>0.05 L/min) (measured or calculated by CKD-EPI formula or Japanese version of CKD-EPI formula for Japanese patients).

• ANC ≥ 1.0x 10^9/L (≥ 1.0 x 10^3/μL, ≥ 1,000/mm3)

• Platelets ≥ 100x10^9/ L (≥ 100 x 10^3/μL, ≥ 100 x 10^3/mm3)

• Hemoglobin (Hb) ≥8.5 g/dl, ≥ 85 g/L, or ≥ 5.3 mmol/L (without transfusion within previous week)

• Serum lipase ≤ 1.5 institutional ULN

  • Recovery from any adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0 of previous anti-cancer therapies to baseline or CTCAE grade 1, except for alopecia CTCAE grade 2, sensory peripheral neuropathy CTCAE grade ≤ 2 or considered not clinically significant.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
  • Life expectancy ≥ 3 months in the opinion of the investigator
  • Of legal adult age (according to local legislation) at screening
  • Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
  • Male or female patients. Women of childbearing potential (WOCBP) and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly.

Exclusion Criteria:

• Previous systemic anti-cancer therapy within the specified timeframe from the last dose intake to the first dose of trial treatment as shown below:

  • Any non-investigational drug, including anti-angiogenic antibodies (bevacizumab or ramucirumab) and anti-EGFR antibodies (cetuximab or panitumumab), within 14 days.
  • Any investigational drug or other antibodies including immune checkpoint inhibitors, within 28 days.

• Radiation therapy within 4 weeks prior to start of treatment. However, palliative radiotherapy for symptomatic metastasis is allowed if completed within 2 weeks prior to start of treatment but must be discussed with the sponsor.

• Any serious concomitant disease or medical condition affecting compliance with Trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal (GI) tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or trial drug administration, and in the judgment of the Investigator, would make the patient inappropriate for entry into the trial. Any history of stroke or myocardial infarction within 6 months prior to screening.

• Known pathological condition of GI tract, liver and pancreas, excluding the disease under study, that may interfere with assessment of drug safety or may increase the risk of toxicity:

  • inflammatory bowel disease
  • chronic pancreatitis
  • other serious GI pathological conditions by judgment of the investigator e.g. autoimmune disease with GI involvement, unexplained active diarrhea CTCAE grade ≥2 according to CTCAE v5.0.

• Known history of human immunodeficiency virus infection.

• Any of the following laboratory evidence of hepatitis virus infection. Test results obtained in routine diagnostics are acceptable if done within 14 days before the informed consent date:

  • Positive results of hepatitis B surface (HBs) antigen
  • Presence of HBc antibody together with HBV-DNA
  • Presence of hepatitis C RNA

• Active concomitant malignancies, other than the one treated in this trial.

• Chronic alcohol or drug abuse or any condition that, in the investigator's opinion, makes the patient an unreliable trial participant or unlikely to comply with the protocol requirements or not expected to complete the trial as scheduled.

• Women who are pregnant, nursing, or who plan to become pregnant while in the trial; female patients who do not agree to the interruption of breast feeding from the start of study treatment to within 30 days after the last study treatment.

• Presence of uncontrolled or symptomatic brain or subdural metastases. Inclusion of patients with brain metastases who have completed local therapy and are considered stable by the investigator, or with newly identified asymptomatic brain metastases at screening will be allowed. Use of corticosteroids is allowed if the dose was stable for at least 1 week before the baseline MRI.

• Patients who are under judicial protection and patients who are legally institutionalized

• Major surgery (major according to the investigator's assessment) performed within 3 weeks prior to treatment start or planned within 3 months after screening, e.g. hip replacement.

• Any of the following cardiac criteria:

  • Resting corrected QT interval (QTc) >470 msec
  • Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
  • Patients with an ejection fraction (EF) <50% or the lower limit of normal of the institutional standard will be excluded. Only in cases where the Investigator (or the treating physician or both) suspects cardiac disease with negative effect on the EF, will the EF be measured during screening using an appropriate method according to local standards to confirm eligibility (e.g., echocardiogram, multi-gated acquisition scan). A historic measurement of EF no older than 6 months prior to first administration of study drug can be accepted provided that there is clinical evidence that the EF value has not worsened since this measurement in the opinion of the Investigator or of the treating physician or both.

• Known hypersensitivity to the trial medication and/or its components i.e. polysorbate 20, sodium citrate, lysine hydrochloride, sucrose, citric acid.