Safety and Efficacy Evaluation of Bosutinib Plus Atezolizumab in Newly Diagnosed Chronic Leukemia Adult Patients

Study Overview
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Brief Summary
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The combination of bosutinib plus atezolizumab in first line treatment in newly diagnosis chronic-phase CML patients could potentially increase molecular responses and therefore treatment discontinuation probabilities in these patients. We propose an Open-Label Phase Ib/II Study of Bosutinib in Combination with Atezolizumab for the Treatment of New Diagnosis Chronic Phase-Chronic Myeloid Leukemia Patients.

Official Title
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Multicenter, Open-label, Phase Ib/II Trial to Evaluate Safety and Efficacy for the Combination of Bosutinib Plus Atezolizumab in Newly Diagnosed Chronic Myeloid Leukemia Patients

Conditions
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Chronic Phase-Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Bosutinib 400 MG Monotherapy
* Drug: Bosutinib 400 MG + Atezolizumab 840 MG in 14 ML Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient ≥ 18 years of age. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Newly Patient with Philadelphia chromosome positive chronic phase CML and BCR-ABL1 transcript detected at diagnosis. ECOG Performance Status of 0, 1, or 2. Adequate hepatic, renal and pancreatic function defined as: Total bilirubin within normal range or Direct bilirubin ≤ 1.5 x ULN, Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN) or ≤5 x ULN if attributable to liver involvement of leukemia, Women of childbearing potential must have a negative pregnancy test documented prior enrollment. Women of childbearing potential and men must be using an adequate method of contraception. Exclusion Criteria: Pregnant or lactating women, Participation in another clinical trial with any investigational drug within 30 days prior to study enrollment, Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), with the exception of hydroxyurea, Period of time since CML diagnosis longer than 6 months, Hypersensitivity to the active substances or to any of the excipients of the bosutinib and/or atezolizumab formulations, Major surgery or radiotherapy within 14 days of enrollment, Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease, Concomitant use of or need for medications known to prolong the QTc interval, Concomitant use with strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin), moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem), or strong CYP3A inducers (rifampin, carbamazepine, phenytoin), History of clinically significant or uncontrolled cardiac disease, including: Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure. Myocardial infarction within the previous 6 months, Symptomatic cardiac arrhythmia requiring treatment, Diagnosed or suspected congenital or acquired prolonged QT history or prolonged QTc. (QTcF should not exceed 500 msec), Grade III or IV fluid retention, Uncontrolled hypomagnesemia or uncorrected symptomatic hypokalemia, due to potential effects on the QTc interval, Uncontrolled or symptomatic hypercalcemia, Recent or ongoing clinically significant gastrointestinal (GI) disorder e.g. Crohn's Disease, Ulcerative Colitis or prior total or partial gastrectomy, Autoimmune or infectious active disease that require treatment, CML patient not in chronic phase at diagnosis, Patients with known atypical transcript. An atypical transcript is defined by the presence of any transcript in the absence of the major transcripts b3a2 (e14a2) and b2a2 (e13a2) or p210 protein, Patients with known resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V). It is not necessary to perform mutation tests on the patient to be included in the study if they were not previously performed, Individuals with an active malignancy, Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive) and/or hepatitis C. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug. Patients with severe renal impairment

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bosutinib-Atezolizumab Combination<br>Drugs to be administered: Bosutinib 400 MG/day Oral Tablet [Bosulif 100mg oral tablets] for 1 year Atezolizumab 1680 mg/28 days [Tecentriq 840 MG in 14 ML Injection] for 1 year | Drug: Bosutinib 400 MG Monotherapy<br>* One cycle (28 days) only with bosutinib 400 mg/day therapy at the beginning of the trial + 12 cycles with bosutinib 400 mg/day therapy after combined therapy<br>* Other names: Bosulif;Drug: Bosutinib 400 MG + Atezolizumab 840 MG in 14 ML Injection<br>* 12 cycles with bosutinib 400 mg/day plus atezolizumab 1680 mg q4w therapy between the monotherapy bosutinib cycles<br>* Other names: Bosulif + Tecentriq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile of bosutinib 400 mg daily in combination with atezolizumab in participants with chronic myeloid leukemia as first line treatments | All Adverse Events, despite their severity or causal relationship with the study medication, will be reported, graded according CTCAE v5.0 and analyzed. | through study completion, approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the Major Molecular Response (MMR) rates | Ratio of patients that reach a Major Molecular Response | up to 2 years | 
| To evaluate the Molecular Response (MR) rates | Ratio of patients that reach a Molecular response | up to 2 years | 
| Percentage of Participants Alive | Percentage of patients that remain alive at different time-points over the total number or patients | at Months 6, 12 and 24 | 
| Number of confirmed MR4 and MR4.5 | Total number of patients that reach MR4 and MR4.5 | up to 2 years | 
| The rate of confirmed MR4 and MR4.5 | Ratio of patients that reach MR4 and MR4.5 | up to 2 years | 
| Number of Complete Cytogenetic Responses (CCyR) | Number of patients that reach a Complete Cytogenetic Responses (CCyR) | At 1 year | 
| The rate of Complete Cytogenetic Response (CCyR) | Ratio of patients that reach a Complete Cytogenetic Responses (CCyR) | At 1 year | 
| Number of days to response (CCyR, MMR, MR4, MR4.5) |  | up to 2 years | 
| The median time to response (CCyR, MMR, MR4, MR4.5) |  | Up to 2 years | 
| The overall estimated probability of response (CCyR, MMR, MR4, MR4.5) |  | Up to 2 years | 
| Number of overall surviving patients |  | Up to 2 years | 
| Number of progression-free survival patients |  | Up to 2 years | 
| Number of failure-free survival patients |  | Up to 2 years | 
| Number of event-free survival patients |  | Up to 2 years | 
| Phenotypical assays of cell characterization |  | Up to 2 years | 
| Phenotypical assays of differentiation, maturation and proliferation NK cells markers |  | Up to 2 years | 
| Phenotypical assays of CD4+ T cells activation markers |  | Up to 2 years | 
| Phenotypical assays of predictive markers of CML relapse |  | Up to 2 years |