BAL0891 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This study is a multiple cohort, multicenter, open-label Phase 1 study with dose-escalation substudies investigating intravenous (IV) BAL0891 as monotherapy, and in combination with carboplatin or paclitaxel, to determine the safety and tolerability of increasing doses of BAL0891 in patients with advanced solid tumors.

Detailed Description
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Substudy 1 (monotherapy dose-escalation cohorts) This study will be initiated with enrollment into Substudy 1 and will estimate the safety, tolerability, PK, and PD of increasing doses of BAL0891 in patients with advanced solid tumors. The starting dose will be 5 mg based on the GLP (Good Laboratory Practice) toxicology studies. Dose escalation will comprise a dose range from a dose of 5 mg up to a maximum absolute dose of 480 mg, with eight nominal dose levels (DLs) of 5 / 10 / 20 / 40 / 80 / 160 / 320 / 480 mg. Intra-patient dose escalations are only allowed for patients enrolled in single-patient DL Cohorts 1.1, 1.2, and 1.3. From DL Cohort 1.4 onwards, the projected maximum dose-escalation factor will be two-fold; if the DL cohort investigates an increased dose, dosing of the patients within the cohort must be separated by at least 7 days. For cohorts in which doses are not increased (including backfill enrollment), patients may be enrolled concurrently. BAL0891 will be administered intravenously (IV) on Day (D) 1 and D8 every 3 weeks (Q3W); for the schedule of assessments of Regimen A. Alternative 21-day or 28-day dosing regimens may be investigated; for the schedule of assessments of Regimens B-D. Substudies 2 and 3 (dose-escalation cohorts for combination regimens) Enrollment into Substudies 2 and 3 may commence as early as first signs of expected target toxicity and/or efficacy with Regimen A (or an alternative monotherapy regimen) have been observed, or alternatively, once the MTD of BAL0891 monotherapy has been assessed. Patients enrolled into Substudies 2 and 3 will be treated with increasing doses of BAL0891 in combination with carboplatin and paclitaxel, respectively, and dose escalation of both BAL0891 and carboplatin/paclitaxel if required will use the same cumulative BLRM-EWOC model as Substudy 1. The starting dose of BAL0891 in combination with carboplatin or paclitaxel will be a safe DL determined in Substudy 1 but not higher than approximately half the MTD. Backfill enrollment of up to a total of 30 additional patients for both substudies (who may be enrolled concurrently) may be used to better estimate the RP2D for each combination if required.

Official Title
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A Phase 1 Study of BAL0891 as Monotherapy and in Combination With Chemotherapy in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: BAL0891
* Combination Product: Carboplatin
* Combination Product: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent signed by the patient prior to any study related procedure indicating that they understand the purpose of, and procedures required for, the study, and are willing to participate in the study. Male or female aged ≥ 18 years. Patients with incurable advanced/metastatic solid tumor disease refractory to or intolerant of existing therapy known to provide clinical benefit for their condition. Note: Patients with non-CNS tumors participating during dose escalation may have inactive CNS metastasis, defined as 4 weeks after either brain metastasis resection or radiation, and a) all residual neurological symptoms resolved to grade ≤ 2; b) on stable doses of dexamethasone, if applicable; and c) follow-up imaging shows no new lesions appearing. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. For patients enrolled from DL1.4 of Substudy 1 onwards and for all patients in Substudies 2 and 3, measurable tumor disease per Response Evaluation Criteria in Solid Tumors 1.1 criteria (RECIST 1.1), i.e., a minimum of one target lesion. Adequate organ functions as indicated by the following Screening visit local laboratory values: Hemoglobin ≥ 9 g/dL (criterion must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 4 weeks) ANC ≥ 2.0 × 109/L; criterion must be met without growth factor (e.g., G-CSF, GM CSF, etc.) administration within the last 2 weeks Platelets ≥ 100 × 109/L Total bilirubin ≤ 1.5 × ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) baseline levels ≤ 1.5 × ULN, with the option for AST/ALT ≤ 3.0 × ULN, or ≤ 5.0 × ULN for patients with liver metastasis, upon accumulating evidence for absence of liver toxicity in biologically active DLs Albumin ≥ 2.8 g/dL CLCR ≥ 60 mL/min (as calculated by the Cockcroft-Gault formula) For women of child-bearing potential, negative serum human chorionic gonadotropin (hCG) Men/women of child-producing/bearing potential must agree to: avoid impregnating a partner or becoming pregnant, respectively, during the study, and for at least 90 days after the last dose of either investigational drug, and comply with the contraception requirements. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-escalation substudy of BAL0891 monotherapy<br>Increasing doses of BAL0891 will be administered IV on D1 and D8 Q3W (Regimen A). BAL0891 will be investigated in a dose range of 5-480 mg with Regimen A. Optionally, and based on cumulative safety, PK, and PD data, BAL0891 may be administered on D1 Q3W (Regimen B), D1 and D15 Q4W (Regimen C), or on D1, D8, and D15 Q4W (Regimen D). | Drug: BAL0891<br>* BAL0891 is a dual inhibitor of threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1)<br>* Other names: TTK-CS-101;|
| Experimental: Dose-escalation substudy of BAL0891 in combination with carboplatin<br>Carboplatin will be dosed at AUC5 Q3W, with an option to use AUC6 (either instead of, or after exploring, AUC5) if the cumulative data collected at that time support a higher dose of carboplatin. | Drug: BAL0891<br>* BAL0891 is a dual inhibitor of threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1)<br>* Other names: TTK-CS-101;Combination Product: Carboplatin<br>* Carboplatin is an Antineoplastic agent<br>|
| Experimental: Dose-escalation substudy of BAL0891 in combination with paclitaxel<br>Paclitaxel will be dosed at 70 mg/m2 on D1, D8, and D15 Q4W, with an option to use 80 mg/m2 (either instead of, or after exploring, 70 mg/m2) if the cumulative data collected at that time support a higher dose of paclitaxel. | Drug: BAL0891<br>* BAL0891 is a dual inhibitor of threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1)<br>* Other names: TTK-CS-101;Combination Product: Paclitaxel<br>* Paclitaxel is a natural product with antitumor activity<br>* Other names: Taxol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Safety is collected through summaries of AE(Adverse Event)s, safety laboratory evaluations, PK evaluations, physical examinations, vital signs, and ECGs using CTCAE v5.0. | 28 (±3) days after last dose, up to 2 years | 
| Number of Participants With the DLT (Dose-limiting toxicity)s as a Measure of maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) | DLTs are collected through BLRM-EWOC. | Within 7 days of End of Treatment, up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) parameters for all subjects | The area under the plasma concentration-time curve (AUC) by PK Sampling | Within 7 days of End of Treatment, up to 2 years | 
| Absolute neutrophil count (ANC) for all subjects | Duration of neutropenia by PD Sampling | Within 7 days of End of Treatment, up to 2 years | 
| Overall response rate (ORR) for all subjects | The proportion of patients with confirmed complete response (CR) or partial response (PR) by RECIST 1.1 | Every 3 months (±14 days) after last dose, up to 2 years | 
| Disease control rate (DCR) for all subjects | The proportion of patients with confirmed CR, PR or stable disease (SD) by RECIST 1.1 | Within 7 days of End of Treatment, up to 2 years | 
| progression-free survival (PFS) for all subjects | Measured from patient enrollment to disease progression date | Within 7 days of End of Treatment, up to 2 years | 
| overall survival (OS) for all subjects | Measured from from patient enrollment to time of death | Within 7 days of End of Treatment, up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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carcinoma, carboplatin, paclitaxel