A Phase 1 study of BAL0891 as monotherapy and in combination with chemotherapy in patients with advanced solid tumors

Receipt of treatment before the first dose of study drug (Cycle 1 D1) within an interval shorter than the following, as applicable:

• One chemotherapy or biological (e.g., antibody, antibody drug-conjugate) cycle interval
• 5 half-lives of any small molecule investigational or licensed medicinal product
• 2 weeks, for any investigational medicinal product (IMP) with an unknown half-life
• 4 weeks of curative radiotherapy
• 7 days of palliative radiotherapy.
• Either receipt of ≥ 4 prior lines of cytotoxic chemotherapy-containing, anti-cancer treatment (both in the [neo]adjuvant and advanced/metastatic setting), or episode(s) of neutropenic sepsis or prolonged antibiotic treatment (> 2 weeks treatment and/or hospitalization for either Grade 4 neutropenia, Grade ≥ 3 neutropenia-associated infection or neutropenic fever) during either of the last two anti-cancer treatments.
• Prior radiation of > 25% of hematopoietic bone marrow volume in long bones, pelvis, and lumbar spine (per Investigator assessment) and/or prior bone marrow/stem cell transplantation.
• Any unresolved (at the time of Screening visit) clinically significant Grade ≥ 2 toxicity (except for Grade 2 alopecia, and Grade 2 platinum-therapy related neuropathy from previous anti-tumor treatment).
• 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 ECG at Screening, including a QTcF > 450 ms for males or > 460 ms for females (mean values from triplicate ECGs).
• Lack of recovery from major (e.g., open abdominal) surgery after 4 weeks, or major elective surgery is planned during the foreseeable duration of the study.
• Concurrent uncontrolled or active infection with human immunodeficiency virus (HIV; known HIV 1/2 antibodies positive).
• Active hepatitis C, active hepatitis B, or chronic hepatitis B with an HBV DNA ≥ 100 IU/mL without current antiviral therapy.

Note: The initial serology testing during the Screening visit for evaluating an active or chronic Hepatitis B infection has to include the following markers: HBsAg, HBcAb and HBsAb. In the event of a positive HBsAg test result, the patient cannot be enrolled. In the event of a positive HBcAb and negative HBsAb test result, an HBV DNA RT-PCR test has to be performed, and the patient can be only enrolled if HBV DNA < 100 IU/mL and the patient receives adequate antiviral therapy.

Note: The serology testing during the Screening visit for evaluating an active or chronic Hepatitis C infection includes Hepatitis C antibody (HepCAb), followed by Hepatitis C virus RNA by PCR if HepCAb is positive. Patients who test HepCA positive but have an HCV RNA negative test result due to prior treatment or natural resolution may be enrolled.

• Severe bacterial, fungal, viral, and/or parasitic infections treated with therapeutic oral or IV medication at the time of first dose of study drug administration.
• Grade 3 adipositas, i.e., BMI ≥ 40 kg/m2.
• For Substudy 2, receipt of prior BAL0891 or contraindicated to receive carboplatin (e.g., history of severe allergic reactions to cisplatin or other platinum-containing compounds, severe bone marrow suppression [baseline ANC < 2.0 × 109/L], or significant bleeding).
• For Substudy 3, receipt of prior BAL0891 or contraindicated to receive paclitaxel (e.g., history of prior severe hypersensitivity reactions to paclitaxel, severe bone marrow suppression [baseline ANC < 2.0 × 109/L]), and/or receipt of mandatory premedications (e.g., H2 antagonists or alternatives, and corticosteroids, diphenhydramine, or alternatives).
• Known hypersensitivity or allergy to any component of the formulations of BAL0891 (e.g., cyclodextrins), carboplatin (for Substudy 2 only), or paclitaxel (for Substudy 3 only).
• Requiring supportive care treatment with hematopoietic growth factors within the 2 weeks prior to treatment allocation.

Note: Biologic response modifiers administered for erythropoiesis (e.g., erythropoietin, darbepoetin alpha) may be administered to patients who experienced severe bone marrow suppression during study treatment. Granulocyte growth factors (e.g., G-CSF, GM-CSF, etc.) will be administered according to the Investigator’s standard practice or American Society of Clinical Oncology (ASCO) guidelines (Smith 2015).

• Treatment with systemic corticosteroids (except for steroidal replacement therapy with 10 mg or less of prednisone or equivalent) or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to first dose of study drug, or anticipated requirement for systemic immunosuppressive medications during the study.

Note: Inhaled, intranasal, intraocular, topical corticosteroids, and intra articular joint injections of corticosteroids are allowed.

• Any other uncontrolled intercurrent illness that would unduly increase the risk of toxicity or limit compliance with study requirements, including but not limited to ongoing or active symptomatic infection, uncontrolled diabetes mellitus, or hepatic, renal, respiratory, or psychiatric illness.
• A history or evidence of psychiatric disorder, substance abuse, or any other clinically significant disorder, condition, or disease that, in the opinion of the Investigator or the Sponsor would pose a risk to the safety of the patient, or would interfere with the study evaluation, procedures, or completion.
  Pregnant or breastfeeding.

≥ 4 prior lines of cytotoxic chemotherapy-containing therapies