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

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

The combination of bosutinib plus atezolizumab in first line treatment in newly diagnosis chronic-phase Chronic Myeloid Leukemia (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.

Study Overview

• Status: Terminated
• Conditions: Chronic Phase-Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Bosutinib 400 MG Monotherapy; Drug: Bosutinib 400 MG + Atezolizumab 840 MG in 14 ML Injection

Detailed Description

The combination of bosutinib and atezolizumab in first line treatment in newly diagnosis chronic-phase Chronic Myeloid Leukemia (CML) patients could potentially increase molecular responses and consequently treatment discontinuation probabilities in these patients. We would like to 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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Begoña Maestro, PhD; Phone Number: 209 0034911 923 700; Email: begona.maestro@ifth.es

Study Locations

• Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female patient ≥ 18 years of age.
2. 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.
3. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
4. Newly Patient with Philadelphia chromosome positive chronic phase CML and BCR-ABL1 transcript detected at diagnosis.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.

6. Adequate hepatic, renal and pancreatic function defined as:

   1. Total bilirubin within normal range or Direct bilirubin ≤ 1.5 x ULN,
   2. 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,
7. 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:

1. Pregnant or lactating women,
2. Participation in another clinical trial with any investigational drug within 30 days prior to study enrollment,
3. Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), with the exception of hydroxyurea,
4. Period of time since CML diagnosis longer than 6 months,
5. Hypersensitivity to the active substances or to any of the excipients of the bosutinib and/or atezolizumab formulations,
6. Major surgery or radiotherapy within 14 days of enrollment,
7. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease,
8. Concomitant use of or need for medications known to prolong the QTc interval,
9. Concomitant use with strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin), moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem), or strong CYP3A inducers (rifampin, carbamazepine, phenytoin),

10. History of clinically significant or uncontrolled cardiac disease, including:

    1. Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure.
    2. Myocardial infarction within the previous 6 months,
    3. Symptomatic cardiac arrhythmia requiring treatment,
    4. Diagnosed or suspected congenital or acquired prolonged QT history or prolonged QTc. (QTcF should not exceed 500 msec),
11. Grade III or IV fluid retention,
12. Uncontrolled hypomagnesemia or uncorrected symptomatic hypokalemia, due to potential effects on the QTc interval,
13. Uncontrolled or symptomatic hypercalcemia,
14. Recent or ongoing clinically significant gastrointestinal (GI) disorder e.g. Crohn's Disease, Ulcerative Colitis or prior total or partial gastrectomy,
15. Autoimmune or infectious active disease that require treatment,
16. CML patient not in chronic phase at diagnosis,
17. 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,
18. 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,
19. Individuals with an active malignancy,
20. Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive) and/or hepatitis C.
21. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug.
22. Patients with severe renal impairment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Bosutinib-Atezolizumab Combination; Drugs to be administered: Bosutinib 400 milligram (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; 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; Other Names: Bosulif; Drug: Bosutinib 400 MG + Atezolizumab 840 MG in 14 ML Injection; 12 cycles with bosutinib 400 mg/day plus atezolizumab 1680 mg q4w therapy between the monotherapy bosutinib cycles; Other Names: Bosulif + Tecentriq

What is the study measuring?

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, up to 7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Evaluate the Molecular Response (MR) Rates	Ratio of patients that reach a Molecular response	7 months
Percentage of Participants Alive	Percentage of patients that remain alive at different time-points over the total number or patients	7 months
Number of Confirmed MR4 and MR4.5	Total number of patients that reach Molecular response 4 (MR4) and Molecular Response 4.5 (MR4.5)	7 months
The Rate of Confirmed MR4 and MR4.5	Ratio of patients that reach MR4 and MR4.5	7 months
Number of Complete Cytogenetic Responses (CCyR)	Number of patients that reach a Complete Cytogenetic Responses (CCyR)	7 months
The Rate of Complete Cytogenetic Response (CCyR)	Ratio of patients that reach a Complete Cytogenetic Responses (CCyR)	7 months
Days to Response (CCyR, MMR, MR4, MR4.5)	Number of days lasted since the beginning of the treatment upt to reach molecular response.	7 months
The Median Time to Response (CCyR, MMR, MR4, MR4.5)	Average elapsed time measured for all included patients since the beginning of the treatment up until reach measurable cytogenetic or molecular response	7 months
Probability of Response (CCyR, MMR, MR4, MR4.5)	The overall estimated probability of reaching complete cytogenetic response or molecular response MMR, MR4 or MR4.5	7 months
Number of Overall Surviving Patients	Number of the overall surviving patients	7 months
Number of Progression-free Survival Patients	The following events are considered disease progression: Acelerated Phase.; Blast Crisis.; CML-related death.	7 months
Number of Failure-free Survival Patients	Number of the failure-free survival patients	7 months
Number of Event-free Survival Patients	Number of the event-free survival patients	7 months
Phenotypical Assays of Cell Characterization	Phenotypical assays of the cell characterization	7 months
Phenotypical Assays of Differentiation, Maturation and Proliferation NK Cells Markers	Phenotypical assays of the differentiation, maturation and proliferation NK cells markers	7 months
Phenotypical Assays of CD4+ T Cells Activation Markers	Phenotypical assays of the CD4+ T cells activation markers	7 months
Phenotypical Assays of Predictive Markers of CML Relapse	Phenotypical markers assessment for relapse included; Cell characterization: NK cells (CD3- CD56+; CD16+ CD56+; TNFα; IFNα; Granzyme b NK-LGL cells (CD56+ CD57+), T-LGL cells (CD3+ CD57+), CD8 TCRα/β, NK markers (NKG2D, KIR2DL2/DL3/DS2, KIR2DL5B).; Differentiation and maturation (NKG2A/CD16) and proliferation (NK67) markers of NK cells.; CD4+ T cells activation markers: CD25 CD69 HLA-DR.; Predictive markers of CML relapse: T regs (CD4+ CD25int-hi CD127low), CD8+ T cells (PD-1/PD-L1) and plasmacytoid dendritic cells (CD86+).	7 months

Collaborators and Investigators

• Sponsor: Fundacion Espanola para la Curacion de la Leucemia Mieloide Cronica
• Collaborators: Pfizer; Roche Farma, S.A
• Investigators: Principal Investigator: Valentin Garcia, Dr., Hospital Ramon y Cajal

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2021
• Primary Completion (Actual): September 24, 2021
• Study Completion (Actual): September 24, 2021

Study Registration Dates

• First Submitted: January 19, 2021
• First Submitted That Met QC Criteria: March 8, 2021
• First Posted (Actual): March 11, 2021

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chronic Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Tyrosine Kinase Inhibitors; Atezolizumab; Bosutinib
• Other Study ID Numbers: ZEROLMC-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No