Chronic Phase-Chronic Myeloid Leukemia
Conditions
Brief summary
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.
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.
Interventions
DRUGBosutinib 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
DRUGBosutinib 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
Sponsors
Pfizer
Roche Farma, S.A
Fundacion Espanola para la Curacion de la Leucemia Mieloide Cronica
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Profile of Bosutinib 400 mg Daily in Combination With Atezolizumab in Participants With Chronic Myeloid Leukemia as First Line Treatments | through study completion, up to 7 months | All Adverse Events, despite their severity or causal relationship with the study medication, will be reported, graded according CTCAE v5.0 and analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Alive | 7 months | Percentage of patients that remain alive at different time-points over the total number or patients |
| Number of Confirmed MR4 and MR4.5 | 7 months | Total number of patients that reach Molecular response 4 (MR4) and Molecular Response 4.5 (MR4.5) |
| The Rate of Confirmed MR4 and MR4.5 | 7 months | Ratio of patients that reach MR4 and MR4.5 |
| Number of Complete Cytogenetic Responses (CCyR) | 7 months | Number of patients that reach a Complete Cytogenetic Responses (CCyR) |
| The Rate of Complete Cytogenetic Response (CCyR) | 7 months | Ratio of patients that reach a Complete Cytogenetic Responses (CCyR) |
| Days to Response (CCyR, MMR, MR4, MR4.5) | 7 months | Number of days lasted since the beginning of the treatment upt to reach molecular response. |
| The Median Time to Response (CCyR, MMR, MR4, MR4.5) | 7 months | Average elapsed time measured for all included patients since the beginning of the treatment up until reach measurable cytogenetic or molecular response |
| Probability of Response (CCyR, MMR, MR4, MR4.5) | 7 months | The overall estimated probability of reaching complete cytogenetic response or molecular response MMR, MR4 or MR4.5 |
| To Evaluate the Molecular Response (MR) Rates | 7 months | Ratio of patients that reach a Molecular response |
| Number of Progression-free Survival Patients | 7 months | The following events are considered disease progression: * Acelerated Phase. * Blast Crisis. * CML-related death. |
| Number of Failure-free Survival Patients | 7 months | Number of the failure-free survival patients |
| Number of Event-free Survival Patients | 7 months | Number of the event-free survival patients |
| Phenotypical Assays of Cell Characterization | 7 months | Phenotypical assays of the cell characterization |
| Phenotypical Assays of Differentiation, Maturation and Proliferation NK Cells Markers | 7 months | Phenotypical assays of the differentiation, maturation and proliferation NK cells markers |
| Phenotypical Assays of CD4+ T Cells Activation Markers | 7 months | Phenotypical assays of the CD4+ T cells activation markers |
| Phenotypical Assays of Predictive Markers of CML Relapse | 7 months | Phenotypical markers assessment for relapse included 1. 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). 2. Differentiation and maturation (NKG2A/CD16) and proliferation (NK67) markers of NK cells. 3. CD4+ T cells activation markers: CD25 CD69 HLA-DR. 4. Predictive markers of CML relapse: T regs (CD4+ CD25int-hi CD127low), CD8+ T cells (PD-1/PD-L1) and plasmacytoid dendritic cells (CD86+). |
| Number of Overall Surviving Patients | 7 months | Number of the overall surviving patients |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bosutinib-Atezolizumab Combination 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
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
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 | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Bosutinib-Atezolizumab Combination |
|---|---|
| Age, Continuous | 47.8 years STANDARD_DEVIATION 14.4 |
| BCR-ABL | 84.9707 IS (%) STANDARD_DEVIATION 83.3527 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 9 / 9 |
| serious Total, serious adverse events | 4 / 9 |
Outcome results
Primary
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.
Time frame: through study completion, up to 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol for safety reasons were reached. Therefore no sufficient data were obtained to conduct an efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib-Atezolizumab Combination | Safety Profile of Bosutinib 400 mg Daily in Combination With Atezolizumab in Participants With Chronic Myeloid Leukemia as First Line Treatments | 55 Total No Adverse events recorded |
Secondary
Days to Response (CCyR, MMR, MR4, MR4.5)
Number of days lasted since the beginning of the treatment upt to reach molecular response.
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Number of Complete Cytogenetic Responses (CCyR)
Number of patients that reach a Complete Cytogenetic Responses (CCyR)
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Number of Confirmed MR4 and MR4.5
Total number of patients that reach Molecular response 4 (MR4) and Molecular Response 4.5 (MR4.5)
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Number of Event-free Survival Patients
Number of the event-free survival patients
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Number of Failure-free Survival Patients
Number of the failure-free survival patients
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Number of Overall Surviving Patients
Number of the overall surviving patients
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Number of Progression-free Survival Patients
The following events are considered disease progression: * Acelerated Phase. * Blast Crisis. * CML-related death.
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Percentage of Participants Alive
Percentage of patients that remain alive at different time-points over the total number or patients
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Phenotypical Assays of CD4+ T Cells Activation Markers
Phenotypical assays of the CD4+ T cells activation markers
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Phenotypical Assays of Cell Characterization
Phenotypical assays of the cell characterization
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Phenotypical Assays of Differentiation, Maturation and Proliferation NK Cells Markers
Phenotypical assays of the differentiation, maturation and proliferation NK cells markers
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
Phenotypical Assays of Predictive Markers of CML Relapse
Phenotypical markers assessment for relapse included 1. 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). 2. Differentiation and maturation (NKG2A/CD16) and proliferation (NK67) markers of NK cells. 3. CD4+ T cells activation markers: CD25 CD69 HLA-DR. 4. Predictive markers of CML relapse: T regs (CD4+ CD25int-hi CD127low), CD8+ T cells (PD-1/PD-L1) and plasmacytoid dendritic cells (CD86+).
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
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
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
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
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
The Rate of Complete Cytogenetic Response (CCyR)
Ratio of patients that reach a Complete Cytogenetic Responses (CCyR)
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
The Rate of Confirmed MR4 and MR4.5
Ratio of patients that reach MR4 and MR4.5
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).
Secondary
To Evaluate the Molecular Response (MR) Rates
Ratio of patients that reach a Molecular response
Time frame: 7 months
Population: The study had to be prematurely terminated due to drug toxicity; the stopping rules detailed in the protocol were reached. Therefore no sufficient data were obtained to conduct the planned efficacy analysis. No study subjects could be analysed for any of the efficacy outcomes. Study has to be prematurely terminated and the analysis could not be done due to lack of data (n=0 Participants).