| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory High-risk Chronic Lymphocytic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or Refractory High-risk Chronic Lymphocytic Leukemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009310 |
| E.1.2 | Term | CLL |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1 Primary Objectives:
To evaluate the safety and pharmacokinetics of ceralasertib:
• Arm A (discontinued): When given as monotherapy in subjects with R/R high-risk CLL who have exhausted other therapeutic options according to local/regional standard of care.
• Arm B: Ceralasertib given in combination with acalabrutinib in subjects with R/R high-risk CLL who are suitable for treatment with a BTK inhibitor and ceralasertib, per investigator’s clinical opinion.
Part 2 Primary Objectives:
• Arm B: To explore ceralasertib in combination with acalabrutinib in subjects with R/R high-risk CLL who are suitable for treatment with a BTK inhibitor and ceralasertib per investigator’s opinion as measured by ORR (CR+partial response [PR]), CR rate, DOR, PFS, and overall survival (OS). |
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| E.2.2 | Secondary objectives of the trial |
Part 1 Secondary Objective:
• To evaluate the preliminary activity of ceralasertib when given as monotherapy and in combination with acalabrutinib, as measured by ORR (CR+PR), CR rate, DOR, PFS and OS in subjects with R/R, high-risk CLL.
Part 2 Secondary Objective:
• To further evaluate the safety and PK of ceralasertib given in combination with acalabrutinib in subjects with R/R, high-risk CLL. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The Eligible subjects will be considered for inclusion in Parts 1 and 2 of the study if they meet all the following criteria:
1. Diagnosis of relapsed or refractory CLL that meets published diagnostic criteria (International Workshop on Chronic Lymphocytic Leukemia [IWCLL] Hallek 2008) and supported/documented by medical records:
a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥B-cell marker (CD19, CD20, or CD23) and CD5.
b. Prolymphocytes may comprise ≤ 55% of blood lymphocytes.
c. Presence of ≥ 5 x 109 B-lymphocytes/L (5000μL) in the peripheral blood (at any point since diagnosis).
2. Provision of signed, written, and dated informed consent form (ICF)
3. CLL subjects must have ≥ 1 of the following high risk prognostic factors to be considered eligible for the study:
From Arm A Part 1:
a. Presence of 17p del
b. Presence of TP53 mutation
c. Presence of 11q del
From Arm B Part 1 and 2:
a. Presence of 11q del and be deemed suitable to receive a BTK inhibitor and ceralasertib per investigator’s
clinical opinion Note: Initially the subject population for Arm B Parts 1 and 2
will be restricted to those subjects with 11q del only, but the population may be expanded to include those with 17p del and TP53 mutation. This decision will be made between investigators and sponsor based on emerging data and the
decision agreed at an SRC meeting and documented in writing.
Subjects will be eligible based on local laboratory karyotyping and fluorescence in situ hybridization (FISH) results and these results will also be retrospectively confirmed by a central laboratory.
Where testing cannot be performed locally for any reason, central laboratory results will be required to confirm eligibility prior to enrollment.
Note: For bothArm A, Part 1 and Part 2 of the study, subjects
must be R/R high -risk CLL and have exhausted other therapeutic options according to local/regional standard of
care . For Arm B, Part 1, and Arm B, Part 2 of the study, subjects must be R/R high-risk CLL (11q del) and be suitable
for treatment with a BTK inhibitor and ceralasertib per investigator’s clinical opinion. Subjects with 17p deletions
and/or TP53 mutations may be enrolled into the study at a later point in time after evaluation of activity of the
combination in subjects with 11q deletions. Enrollment of these subjects will require approval from the Sponsor.
4. Meet the following laboratory parameters:
Adequate hematologic function defined as independent of transfusion
and growth factor support for ≥14 days before screening, :
a. ANC >1500 cells/mm3 (1.5 x 109/L)
b. Platelet count >75,000 cells/mm3 (75 x 109/L)
c. Hemoglobin ≥9.0 g/dL
d. AST (SGOT) ALT (SGPT) ≤2.5 x upper limit of normal (ULN).
e. Total bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin in which case direct bilirubin should be <1.5 x ULN) )
f. Albumin >33 g/L.
g. Alkaline phosphatase <2.5 x ULN
h. Estimated creatinine clearance using standard methodology (ie, eGFR using Cockcroft-Gault) ≥45 mL/min.
5. Active disease meeting ≥1 of the following IWCLL 2008 criteria for requiring treatment:
a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin <10 g/dL and/or thrombocytopenia (platelets >75,000 cells/mm3 (75 x 109/L)
b. Massive (ie, ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
c. Massive nodes (ie, ≥10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy.
d. Progressive lymphocytosis with an increase of >50% over a 2-month period or a lymphocyte doubling time (LDT) of <6 months. LDT may be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of 2 weeks over an observation period of 2-3 months. In subjects with initial blood lymphocyte counts of <30 x 109/L (30,000μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (eg, infections), should be excluded.
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy.
f. Constitutional symptoms documented in the subject's medical records/chart with supportive objective measures, as appropriate, defined as ≥1of the following disease related symptoms or signs:
i. Unintentional weight loss ≥10% within the previous 6 months before screening.
ii. Significant fatigue (ie, Eastern Cooperative Oncology Group [ECOG] performance status 2 or worse, inability to work or perform usual activities).
iii. Fevers > 100.5°F or 38°C for ≥2 weeks before screening without evidence of infection.
iv. Night sweats >1 month before screening without evidence of infection.
6. Must have received ≥1 prior therapy for treatment of their disease.
7. Men and women ≥18 years of age.
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|
| E.4 | Principal exclusion criteria |
Subjects will be ineligible for this study (both parts) if they meet
any of the following criteria:
1. A diagnosis of ataxia telangiectasia
2. Any prior exposure to an ATR inhibitor or known hypersensitivity to an excipient of the product
3. History of prior malignancy except for the following:
a. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician
b. Adequately treated lentigo malignant melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer
c. Adequately treated carcinoma in situ without current evidence of disease
4. As judged by the investigator, any evidence of severe or uncontrolled systemic disease
5. Known history of infection with human immunodeficiency virus (HIV)
6. Serologic status reflecting active hepatitis B or C infection
7. Undergone any of the following procedures or experienced any of the following conditions currently or in the preceding 6 months: coronary artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris,etc
8. Current refractory nausea and vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass
9. History of CNS lymphoma, leptomeningeal disease or spinal cord compression
10. History of severe allergic or anaphylactic reactions to kinase inhibitors or history of hypersensitivity to active or inactive excipients of ceralasertib or acalabrutinib or drugs with a similar chemical structure or class to ceralasertib or acalabrutinib
11. Presence of a GI ulcer diagnosed by endoscopy within 3 months before screening
12. Any clinically significant pre-existing renal disease or high risk of developing renal impairment.
13. Major surgical procedure within 28 days before first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
14. Unresolved toxicities from prior anticancer therapy, ≥ Grade 2 Common Terminology Criteria for Adverse Events (CTCAE), with the exception of alopecia
15. Cytomegalovirus (CMV) positive- CMV testing at screening must include serology testing for CMV immunoglobulin (Ig) G, CMV IgM, and CMV PCR testing
16. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
17. Cardiac dysfunction as defined as: Myocardial infarction within 6 months of study entry, NYHA class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias or a known history of reduced left ventricular ejection fraction (LVEF) <55%
18. Mean resting corrected QT interval (QTc) calculated using Fridericia's formula (QTcF) >470 msec obtained from 3 electrocardiograms (ECGs) in 24 hours
19. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block)
20. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age
21. Patients at risk of brain perfusion problems, (eg, carotid stenosis)
22. Patients with relative hypotension (<100/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of >20mm Hg
23. Uncontrolled hypertension requiring clinical intervention
24. Any therapeutic antibody within 4 weeks of first dose of study drugs
25. Prior use of standard anti-lymphoma therapy or radiation therapy within 14 days of receiving the first dose of study drug
(not including palliative radiotherapy). Patients must have recovered from acute toxicity due to prior treatment
26. Ongoing immunosuppressive therapy, including systemic (eg, intravenous or oral) corticosteroids for treatment of lymphoid cancer or other conditions
27. Receiving or having received concomitant medications, herbal supplements and/or foods that that significantly modulate cytochrome P450 (CYP) 3A4 or P-glycoprotein 1 (Pgp) activity (wash out periods of 2 weeks, but 3 weeks for St John’s Wort). Note: These include common azole antifungals, macrolide antibiotics and other medications listed in Appendix 4
28. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of study drug
29. This criterion only applies to subjects enrolled into Arm B
Parts 1 and 2 - Requires treatment with proton-pump inhibitors
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety of AZD6738: Ongoing evaluation of Adverse Events throughout all study visits: Type, frequency, severity, timing of onset, duration, and relationship to study drug of any treatment-emergent adverse events (TEAEs) or abnormalities of laboratory tests, serious adverse events (SAEs), DLTs, or adverse events (AEs) leading to discontinuation of study treatment.
Pharmacokinetic Data: The Sparse PK data from ceralasertib monotherapy is will be characterized using a population-based analysis. Data from other studies may also be included in this analysis. The
results of any such analyses will be reported separately from the
clinical study report (CSR).
Rich PK sampling will be performed on all subjects receiving the ceralasertib+acalabrutinib combination and plasma PK will be characterized using a non-compartmental analysis (NCA) and the NCA PK parameter listed
in the protocol will be calculated and reported.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety of ceralasertib: Ongoing evaluation of Adverse Events throughout all study visits
Pharmacokinetic Data:
Time Points for Ceralasertib Monotherapy (discontinued)
• Cycle 1 Days 1 and 22: Predose, 1, 4 and 8 hours postdose
Time Points for Ceralasertib+Acalabrutinib
Combination
• AZD6738: Cycle 2 Days 1 and 7: Predose, 15 mins and 1, 2, 4, 8 and 10-12 hours postdose.
• Acalabrutinib: Cycle 1 Days 7 and cycle 2 days 1 and 7: predose and approximately 1, 2, 4 and 6 hours postdose |
|
| E.5.2 | Secondary end point(s) |
Preliminary activity of ceralasertib measured by ORR (CR+PR), CR rate, DOR, PFS and OS as a single agent and in combination with acalabrutinib in subjects with R/R high risk CLL who have exhausted other therapeutic options according to local/regional standard of care.
Safety of ceralasertib: further evaluation of safety of ceralasertib as a single agent and in combination with acalabrutinib.
Pharmacokinetic Data: Further characterization of the PK profile of ceralasertib as a single agent and in combination with acalabrubitinib |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety of ceralasertib: Ongoing evaluation of Adverse Events throughout all study visits
Pharmacokinetic Data:
Timepoints for ceralasertib monotherapy (discontinued)
• Cycle 1 Days 1 and 22: Predose, 1, 4 and 8 hours postdose
Timepoints for ceralasertib+acalabrutinib combination
• ceralasertib: Cycle 2 Days 1 and 7: Predose, 15 mins and 1, 2, 4, 8 and 10-12 hours postdose.
• Acalabrutinib: Cycle 1 Days 7 and cycle 2 days 1 and 7: predose and approximately 1, 2, 4 and 6 hours postdose. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study for this protocol is when the last subject on the study has completed the last study visit, including follow-up procedures or has been transitioned to a roll over protocol. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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