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Title Phase Ib / II study of BAY 1000394 in combination with cisplatin / etoposide or carboplatin/etoposide as first-line therapy in subjects with extensive disease small cell lung cancer

IRB BAY1512

CC 12-1139

Hospital Main Campus

Stage N/A

Phase Phase 1, Phase 2

Disease Lung

Drug BAY 1000394, Carboplatin, Cisplatin, Etoposide

Description

1. Phase Ib part of the study
   • Primary: Determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose of BAY 1000394 in combination with cisplatin / etoposide or carboplatin / etoposide chemotherapy in 2 separate cohorts in parallel
   • Secondary: Assess the biomarker response profile of BAY 1000394, overall survival, progression-free survival, response rate, duration of response, stable disease and disease control rate
2. Phase II part of the study
   • Primary: Evaluate the response rate in subjects with extensive disease SCLC receiving first-line cisplatin / etoposide or carboplatin / etoposide chemotherapy in combination with BAY 1000394. Tumor response will be evaluated based on RECIST 1.1. Tumor measurements will be made at baseline and then every 2 cycles, ie every 6 weeks based on 21-day cycles, until progressive disease will occur
   • Secondary: Determine the tolerability, safety profile, biomarker response profile, overall survival, progression-free survival, duration of response, and stable disease and disease control rate for the combination of BAY 1000394 and chemotherapy and subsequent maintenance with BAY 1000394

Inclusion Criteria

1. Male or female subjects aged ≥ 18 years
2. Histologically or cytologically confirmed, extensive disease SCLC
3. At least 1 solid tumor lesion measurable by computer tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST 1.1 (see Section 14.7). Subjects with non-measurable disease according to RECIST 1.1 can be included in the Phase Ib part of the study
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1 (see Section 14.6)
5. Life expectancy of at least 12 weeks
6. Serum sodium ≥ 130 mmol/L
7. Adequate bone marrow, liver, and renal functions as assessed by the following laboratory requirements to be conducted within 14 days prior to the first dose of study drug:
   • Hemoglobin ≥ 9.0 g/dL
   • Absolute neutrophil count (ANC) ≥ 2 x 10⁹/L
   • Platelet count ≥ 100 x 10⁹/L
   • Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
   • ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN for subjects with liver involvement of their cancer)
   • INR and PTT ≤ 1.5 x ULN
   • Estimated glomerular filtration rate ≥ 60 mL/min per 1.73 m² according to the Modification of Diet in Renal Disease Study Group (MDRD) formula (see Section 14.8)
8. Negative serum pregnancy test must be obtained within 7 days prior to the start of treatment in women of childbearing potential. Negative results must be available prior to study drug administration
   • Women of childbearing potential and men must agree to use adequate barrier birth control measures from the time of signing of the informed consent form until at least 3 months after the last study drug administration or 6 months after last chemotherapy administration, whichever comes last. In addition, during chemotherapy treatment phase, partners of sexually active subjects should be instructed to use effective contraceptive measures. The investigator or a designated associate is requested to advise the subject on how to achieve adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care. These procedures should be documented in source documents. Postmenopausal women are defined as::
   1. Age > 50 years with amenorrhea for at least 12 months or
   2. Age ≤ 50 years with 6 months of spontaneous amenorrhea and follicle stimulating hormone level within postmenopausal range (>40 mIU/mL) or
   3. Bilateral oophorectomy

   Additional adequate contraception which includes hormonal contraception with implants or combined oral contraceptives, certain intrauterine devices, bilateral tubal ligation, hysterectomy, or vasectomy of the partner is allowed as long as a barrier method is also being used.

9. Subjects with a history of hypertension should be on a stable anti-hypertensive treatment for more than 7 days prior to the first dose of study drug
10. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study-specific procedures

Exclusion Criteria

1. Prior systemic anticancer therapy
2. Prior radiotherapy (local palliative radiotherapy is permitted)
3. Any anticoagulation therapy
4. Known hypersensitivity to any of the study drugs or excipients of the preparations or any agent given in association with this study
5. History of cardiac disease: congestive heart failure > NYHA Class II, unstable angina (anginal symptoms at rest), any episodes of angina or history of myocardial infarction, cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted), previous venous or arterial thrombotic events, pulmonary embolism)
6. Moderate or severe hepatic impairment, i.e. Child-Pugh class B or C
7. Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
8. Active clinically serious infections of CTCAE > Grade 2 (Section 14.5)
9. Symptomatic metastatic brain or meningeal tumors. Subjects with asymptomatic brain metastases must not be on acute steroid therapy or taper off steroid therapy (chronic steroid therapy is acceptable provided that the dose is stable for 4 weeks prior to study entry and following screening CT / MRI scan). Subjects with neurological symptoms should undergo a CT / MRI scan of the brain to exclude new or progressive brain metastases. Spinal cord metastasis is acceptable
10. Seizure disorder requiring therapy (such as steroids or anti-epileptics)
11. History of organ allograft
12. Evidence or history of bleeding disorder, i.e. any hemorrhage / bleeding event of CTCAE > Grade 2 (Section 14.5) within 4 weeks prior to the first dose of study drug
13. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management)
14. Serious, non-healing wound, ulcer, or bone fracture
15. Subjects on dialysis
16. Sensory neuropathy with sensory alterations or paresthesia (including tingling), interfering with function (≥ CTCAE Grade 2) (Section 14.5)
17. Previous or coexisting cancer that is distinct in primary site or histology from the cancer evaluated in this study EXCEPT cervical cancer in-situ, treated basal cell carcinoma, superficial bladder tumors [Ta and Tis], or any cancer curatively treated > 3 years prior to study entry
18. Any condition that is unstable or could jeopardize the safety of the subject and his/her compliance in the study
19. Subjects unable to swallow oral medications
20. Any malabsorption condition
21. Unresolved specific chronic toxicity CTCAE > Grade 2 (excluding cases of alopecia) (Section 14.5)

1. Major surgery, open biopsy, or significant trauma within 4 weeks prior to the first dose of study drug is excluded
2. Autologous bone marrow transplant or stem cell rescue within 4 months prior to first dose of study drug is not allowed
3. Investigational drug treatment outside of this study during or within 4 weeks prior to study entry. Toxic effects of previous investigational drug treatment have to be normalized
4. Prior exposure to any of the study drugs
5. Substance abuse, medical, psychological, or social conditions that may interfere with the subjects participation in the study or evaluation of the study results

1. Pregnant or breast-feeding women. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the first dose of study drug