Summary

Eligibility
for people ages 18-130 (full criteria)
Location
at UCLA
Dates
study started
estimated completion

Description

Summary

This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 monotherapy or with combination agent(s) in relapsed/refractory acute myeloid leukaemia (AML) patients or treatment-naïve AML patients not eligible for intensive induction therapy. The study will also explore the potential clinical activity by assessing anti-tumour activity in patients. The study will be conducted in two parts, designated Part A, dose escalation, and Part B, dose expansion

Official Title

A Phase I/II, Open-Label, Multicentre 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 as Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory Acute Myeloid Leukaemia Patients Not Eligible for Intensive Induction Therapy.

Details

This is a Phase I/II clinical study to determine the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD2811 monotherapy or with combination agent(s) in relapsed/refractory acute myeloid leukaemia (AML) patients or treatment-naïve AML patients not eligible for intensive induction therapy. The study will also explore the potential clinical activity by assessing anti-tumour activity in patients. The study will be conducted in two parts, designated Part A, dose escalation, and Part B, dose expansion. Patients will be enrolled in either Part A or Part B according to the Investigator's judgment of the most appropriate treatment for the individual patient and slot availability.

Part A - Dose Escalation

Arm 1 - Day 1 and 4 monotherapy dose escalation:

Approximately 48 evaluable treatment-naïve AML patients not eligible for intensive induction therapy or relapsed/refractory AML patients will be enrolled in Arm 1 and Arm 2 of the monotherapy escalation in Part A of this study.

The dose escalation and de-escalation plan for evaluating AZD2811 will follow the Bayesian Adaptive Design scheme which combines prior expectations about the dose toxicity relationship and applies the data at the end of each cohort to recommend a dose and schedule for the next cohort. The total number of patients will depend upon the number of dose escalations, de-escalations, and schedule changes necessary. At least 3 and up to 6 evaluable patients will be required for each dose cohort.

Patients will receive a single 2- or 4- hour IV infusion on Day 1 and Day 4 of each 28-day cycle. Dosing frequency and schedule may be adjusted during the study on the basis of emerging safety and pharmacokinetic data.

Arm 2 - Day 1, 4, 15, and 18 monotherapy dose escalation:

A Day 1, 4, 15, and 18 every 4 weeks or 28 days (Q4W) schedule will be investigated in Arm 2. The proposed starting dose for this schedule is 300 mg/infusion AZD2811 on Day 1, 4, 15 and 18 (i.e. cumulative dose 1200 mg/Q4W). This starting dose is less than daily doses shown to be tolerated in the AML setting, and the cumulative cycle dose/Q4W does not exceed the highest dose shown to be tolerated (600 mg/infusion Day 1, 4 cumulative 1200 mg Q4W).

Combination Escalation:

AZD2811 can be escalated (in the combination setting) independent of the monotherapy dose explored, after thorough examination of the available safety data. The combination therapy exploration will not impact the dose to be further explored in the monotherapy setting nor will the monotherapy impact the dose in the combination setting. As such, the number of cohorts in the monotherapy setting can differ from the number of cohorts in the combination setting. The safety observations of the monotherapy will be considered by the Safety Review Committee (SRC) in the overall decision-making process for subsequent dose exploration decision.

Azacitidine Combination:

A starting dose of 400 mg of AZD2811 will be used for investigation in combination with the standard dose of the hypomethylating agent (HMA) azacitidine. In this dose escalation part, approximately 12-15 evaluable treatment-naïve AML patients not eligible for intensive induction therapy or relapsed/refractory AML will be enrolled and dosed in ascending doses of AZD2811 and standard dose of azacitidine at 75 mg/m² subcutaneously (SC) in all territories or optionally/alternatively by IV in the United States (US) as per national prescribing information.

AZD2811 will be administered over 2 hours for doses up to and including 600 mg and over 4 hours for doses exceeding 600 mg on Days 1 and 4 of each 28-day cycle. Patients will receive 75 mg/m² of azacitidine on Days 1 through 7 or for 5 consecutive weekdays (Days 1 through 5) with a treatment holiday on the two weekend days (Days 6 and 7), and azacitidine dosing on the first 2 weekdays of the next week (Days 8 and 9) of each 28-day cycle.

A rolling 6 design will be applied to the AZD2811 + HMA combination group which allows accrual of 3 to 6 patients concurrently onto a dose level based on the numbers of patients who are currently enrolled and evaluable, who experience a DLT, and who remain at risk of developing a DLT.

Venetoclax Combination:

Approximately 18-21 evaluable relapsed/refractory AML patients will be enrolled and dosed with AZD2811 and venetoclax. In cohort 1v, AZD2811 will be administered at 200 mg IV on Days 1 and 4 every 28 days (Q4W) and venetoclax will be given 100 mg orally (PO) on Day 1 and 200 mg (PO) with a meal and water on Days 2- 28 for the 1st cycle. The third patient in cohort 1 (AZD2811 at 200 mg) will only be enrolled after the first 2 patients have received ≥ 2 weeks of treatment and have shown no evidence of toxicity observed to be compatible with a DLT, and further dose escalations of AZD2811 will occur at the discretion of the Safety Review Committee (SRC)

The dose of AZD2811 can be escalated (in the combination setting) independent of the monotherapy dose explored, after thorough examination of the available safety data of the current and the previous cohorts. The combination therapy exploration will not impact the dose further explored in the monotherapy setting nor will the monotherapy impact the dose in the combination setting. As such, the number of cohorts in the monotherapy setting can differ from the number of cohorts in the combination setting. The safety observations of the monotherapy will be considered by the Safety Review Committee (SRC) in the overall decision-making process for subsequent dose exploration decision.

Part B - Dose Expansion

Part B will include up to 80 treatment-naïve AML patients not eligible for intensive induction therapy at the MTD in AZD2811 monotherapy (Group 1, 40 patients) and AZD2811 the combination setting (Group 2, 40 patients) in order to further explore the tolerability, PK and clinical activity at this dose.

Keywords

Acute Myeloid Leukaemia AML AZD2811 AZD1152 AZD1152 hQPA barasertib azacitidine VIDAZA® venetoclax VENCLEXTA® Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Pyrazole

Eligibility

You can join if…

Open to people ages 18-130

for All Patients:

  1. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling or analyses.
  2. ≥ 18 years of age
  3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
  4. Prior treatment with hydroxyurea (up to 24 hours before study treatment) is allowed.
  5. Adequate organ system function as outlined below:
  6. PT/PTT ≤1.5 x upper limit of normal (ULN)
  7. Total bilirubin ≤1.5 x ULN. Patients with documented Gilbert's Syndrome who have serum bilirubin ≤3 x the ULN may be enrolled, unless there is evidence of hemolytic anemia
  8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ˂2.5 × ULN if no liver involvement or ≤5 times the ULN with liver involvement
  9. Creatinine ≤1.5 x ULN, OR calculated or measured creatinine clearance ≥50 mL/min as calculated by the Cockcroft-Gault method, OR 24-hour measured urine creatinine clearance ≥50 mL/min
  10. Other comorbidity that the Investigator judges incompatible with intensive remission induction chemotherapy, which must be documented by the study monitor.
  11. Females should be using adequate contraception should not be breast feeding and must have a negative serum pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
  12. Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
  13. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
  14. Sexually active male patients should be willing to use barrier contraception i.e., condoms. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential, unless the male patient is abstaining from sexual intercourse.

Part A (Dose Escalation) Inclusion Criteria:

  1. AML patients who have relapsed or are refractory to standard therapies.
  2. AML patients who are unlikely to demonstrate rapid progression such that they would be unable to complete the first cycle of therapy.
  3. Adults with previously untreated confirmed diagnosis of AML (bone marrow blasts ≥ 20%) for whom monotherapy with AZD2811 is considered appropriate and are not suitable for intensive induction therapy based on the following:
  4. ≥75 years, or
  5. <75 years of age with clinically significant cardiac or pulmonary dysfunction unrelated to leukaemia, as reflected by at least 1 of the following criteria:
  6. Left ventricular ejection fraction (LVEF) ≤50%
  7. Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% of expected
  8. Forced expiratory volume 1 (FEV1) ≤65% of expected
  9. Chronic stable angina

Part B (Dose Expansion) Inclusion Criterion

  1. Adults with previously untreated confirmed diagnosis of AML per World Health Organization (WHO) and European Leukemia Net (ELN) criteria (bone marrow blasts ≥ 20%) who are not suitable for intensive induction therapy based on the following:
  2. ≥75 years, or
  3. <75 years of age with clinically significant cardiac or pulmonary dysfunction unrelated to leukaemia, as reflected by at least 1 of the following criteria:
  4. Left ventricular ejection fraction (LVEF) ≤50%
  5. Diffusing capacity of the lungs for carbon monoxide (DLCO) ≤65% of expected
  6. Forced expiratory volume 1 (FEV1) ≤65% of expected
  7. Chronic stable angina

You CAN'T join if...

Patients must not enter the study if any of the following exclusion criteria are fulfilled

  1. Treatment with any of the following:
  2. Any investigational agents, experimental antibody or antibody drug conjugates, or study drugs from a previous clinical study within 3-4 weeks of said prior investigational agent(s) with regard to the first dose of study treatment on this protocol.
  3. Any other chemotherapy, immunotherapy or anticancer agents within 2 weeks of the first dose of study treatment
  4. Any haematopoietic growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF]) within 7 days of the first dose of AZD2811 with or without azacitidine or pegylated G-CSF (pegfilgrastim) or darbepoetin within 14 days of the first dose of study treatment.
  5. Prescription or non-prescription drugs or other products known to be strong inhibitors/inducers of CYP3A4 that cannot be discontinued prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug. Washout periods should be a minimum of 5 half-lives depending on the medication.
  6. Patients who have undergone allogeneic stem cell transplant within 12 months are excluded. If allogeneic transplant was > 12 months ago, then they are not excluded as long as they are off all immunosuppression and have no signs or symptoms of active graft versus host disease.
  7. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
  8. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment.
  9. Presence of, or history of leptomeningeal disease.
  10. As judged by the Investigator, any evidence of: a) severe or uncontrolled systemic diseases (e.g., severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease]); or other malignancy (like advanced malignant hepatic tumours); b) current unstable or uncompensated respiratory or cardiac conditions; c) uncontrolled hypertension; d) history of, or active, bleeding diatheses (e.g., haemophilia or von Willebrand disease); e) patients with inflammatory bowel disease (e.g., Crohn's or colitis ulcerosa); uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment); or f) IV anti-infective treatment within 2 weeks before first dose of study treatment unless clear evidence would indicate that despite the clinical symptoms no infection took place.
  11. Any of the following cardiac criteria:
  12. Congestive heart failure (CHF) per New York Heart Association (NYHA) classification > Class II
  13. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
  14. Unstable angina or new-onset angina
  15. QTcF interval > 450 ms (for male subjects) or >470 ms (for female subjects) on screening ECG
  16. Active non-infectious skin disease (including rash, dermatitis, or psoriasis, but excluding stable plaque psoriasis from the definition of active disease). Patients with a rash that is biopsy-proven leukaemia or with pressure ulcers are not excluded. Patients with petechiae from thrombocytopenia or patients with drug related rashes that are improving are not excluded.
  17. Patients with a known hypersensitivity to azacitidine or mannitol (Combination patients only).
  18. History of hypersensitivity to active or inactive excipients (e.g., PEG) of any drug in the study or drugs with a similar chemical structure or class to those investigated in the study.
  19. Known history of infection with human immunodeficiency virus (HIV)
  20. . Serologic status reflecting active hepatitis B or C infection:
  21. Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before enrolment. Those who are hepatitis B surface antigen positive or hepatitis B polymerase chain reaction (PCR) positive will be excluded.
  22. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrolment. Those who are hepatitis C PCR positive will be excluded.

Additional exclusion criteria - venetoclax combination:

  1. WBC count ≤ 25,000 cells/mm³ (25 x 10 exp 9/L); use of leukapheresis or hydroxyurea (48 hours) before venetoclax initiation is allowed to achieve this entry criterion.
  2. AML with known active central nervous system involvement.
  3. Chronic respiratory disease that requires continuous oxygen use.
  4. Previous venetoclax exposure that ended due to venetoclax toxicity.
  5. In addition to strong CYP3A inhibitor/inducers, moderate CYP3A inhibitor/inducers and P-gP inhibitors cannot be discontinued prior to Day 1 of dosing and withheld throughout the first 4 weeks of study start. Washout periods should be a minimum of 5 half-lives depending on the medication.
  6. Patient consumed grapefruit, grapefruit products, Seville oranges (including marmalades containing Seville oranges) or star fruit within 3 days before the initiation of venetoclax.

Locations

  • Research Site accepting new patients
    Milwaukee Wisconsin 53326 United States
  • Research Site accepting new patients
    Denver Colorado 80218 United States

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
AstraZeneca
ID
NCT03217838
Phase
Phase 1
Study Type
Interventional
Last Updated