Phase 1b multi-indication study of anetumab ravtansine (BAY 94-9343) in patients with
mesothelin expressing advanced or recurrent malignancies

Anetumab ravtansine is an antibody-drug conjugate (ADC) targeting mesothelin
which has demonstrated favorable safety profile and improvement in objective
response rate in preclinical and phase I studies in solid tumors. The
potential for anetumab ravtansine to impart clinical benefit in other advanced
solid tumors, for which there is a high unmet medical need for effective
treatment options.

The key purpose of Safety lead in part of this study is to determine the
maximum tolerable dose of anebumab ravtansine in combination with cisplatin for
treatment of mesothelin-expressing cholangiocarcinoma, and similar for the
combination with gemcitabin for the treatment of mesothelin-expressing
adenocarcinoma of the pancreas.
The key purpose of Main study is to assess efficacy and safety of anetumab
ravtansine in treatment of mesothelin-expressing advanced solid tumors.

This is a Phase 1b single arm, multi-indication study of anetumab ravtansine
monotherapy in mesothelin positive tumors including NSCLC
adenocarcinoma, TNBC, gastric adenocarcinoma including GEJ cancer, thymic
carcinoma, and of anetumab ravtansine in combination with
cisplatin in mesothelin positive cholangiocarcinoma, and in combination with
gemcitabine in mesothelin positive pancreatic adenocarcinoma.

The study is composed of the following periods:
- Prescreening for mesothelin expression testing
- Full screening
- Treatment (for cholangiocarcinoma and pancreatic adenocarcinoma separate
safety lead-in phases are included for determination of MTD for the combination
treatments)
- Active follow-up (mandatory safety follow-up visit and efficacy follow-up
visits, if applicable)
- Long-term follow-up

Monotherapy indications: NSCLC adenocarcinoma, TNBC, gastric adenocarcinoma
including GEJ cancer, thymic carcinoma
a) Anetumab ravtansine 6.5 mg/kg every 21 days (1 cycle)

Chemotherapy combination indication: cholangiocarcinoma
a) Safety lead-in for determination of MTD.
b) Main study: anetumab ravtansine at MTD followed by cisplatin 25 mg/m2.

Anetumab ravtansine will be given on Day 1 of a 21-day cycle.
Cisplatin will be given on Day 1 and Day 8 of a 21-day cycle.

Chemotherapy combination indication: pancreatic adenocarcinoma
a) Safety lead-in for determination of MTD.
b) Main study: anetumab ravtansine at MTD and gemcitabine 1000 mg/m2.

Anetumab ravtansine will be given on Day 1 of a 21-day cycle.
Gemcitabine will be given on Day 1 and Day 8 of a 21-day cycle.

Treatment with anetumab ravtansine may have therapeutic benefit but this cannot
be guaranteed.
Most common risks for anetumab ravtansine are nausea, fatigue, vomiting,
anorexia, diarrhea, peripheral neuropathy, increased ALT and AST, corneal
epitheliopathy.
Most common risks for cisplatin are leukopenia, thrombocytopenia, anaemia,
anorexia, nausea, vomiting, diarrhea, hearing impairment, renal failure,
nephrotoxicity, hyperuricaemia, fever
Most common risks for gemcitabin are leucopenia, thrombocytopenia, anaemia,
dyspnoea vomiting, nausea, skin rash, alopecia , elevated AST, ALT and ALP,
haematuria, proteinuria, fever, edema
Weekly visits with blood tests prior to drug administration and additional
sampling at selected visits, and physical exams. Visits will continue until
disease progresses, further follow up is done via 3 monthly telephone contacts.
Examination including eye examination, 2 patient questionnaires, ECG and
radiological tumor assessments will be performed at specific visits.