| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
- Relapsed/Refractory (R/R) de novo TP53 ABC (non-GCB) or GCB diffuse large B-cell lymphoma (DLBCL)
- R/R TP53 chronic lymphocytic leukemia (CLL) naïve to prior Bruton's tyrosine kinase (BTK) inhibitor
- R/R DLBCL with non-germinal center B-cell like(GCB) subtype
- R/R DLBCL with double-expressor lymphoma subtype |
|
| E.1.1.1 | Medical condition in easily understood language |
- Relapsed/Refractory Diffuse Large B-cell Lymphoma
- Relapsed/Refractory 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 | PT |
| E.1.2 | Classification code | 10012822 |
| E.1.2 | Term | Diffuse large B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012821 |
| E.1.2 | Term | Diffuse large B-cell lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Phase 1b:
- To determine the KRT-232 maximum tolerated dose/ maximum administered dose (MTD/MAD) and recommended Phase 2 dose (RP2D) in combination with acalabrutinib in subjects with R/R DLBCL (Cohort 1) or R/R CLL (Cohort 2)
- To determine the safety and tolerability of KRT-232 in combination with acalabrutinib in subjects with R/R DLBCL (Cohort 1) or R/R CLL (Cohort 2)
Phase II:
- Cohort 1 (R/R DLBCL): To determine the complete response (CR) rate in R/R DLBCL.
- Cohort 2 (R/R CLL): To determine the rate of CR/complete remission with incomplete hematologic recovery (CRi) in R/R CLL. |
|
| E.2.2 | Secondary objectives of the trial |
Phase Ib:
- To monitor the PK of KRT-232 and acalabrutinib
Phase II:
- Cohort 1 (R/R DLBCL): To determine the overall response rate (ORR) for R/R DLBCL subjects
- Cohort 2 (R/R CLL): To determine the ORR for R/R CLL subjects
- To evaluate the duration of response (DOR) among subjects who achieve a response of PR or better by cohort.
- Cohort 2 (R/R CLL): To determine the rate of measurable residual disease (MRD)
- To determine the safety and tolerability of KRT-232 in combination with acalabrutinib
- To monitor the PK of KRT-232 and acalabrutinib using sparse sampling. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adults ≥18 years of age;
2. Patient population:
Cohort 1 (R/R DLBCL):
a) Histologically confirmed diagnosis of de novo TP53^wt ABC (non-GCB) or GCB DLBCL based on 2016 WHO Classification;
i) Phase 2: 25 or more subjects with non-GCB and 10 or more subjects with double-expressor lymphoma will be enrolled as described in Section 10.2 of the study protocol;
b) R/R DLBCL after treatment with at least 2 prior lines of systemic therapy or at least 1 prior line of systemic therapy in subjects who are ineligible for hematopoietic stem cell transplantation (autologous or allogeneic) for reasons other than active disease;
c) At least 1 measurable site of disease on computed tomography (CT) (defined as >1.5 cm in longest transverse diameter of a lesion [LDi]) and clearly measurable in 2 perpendicular dimensions);
Cohort 2 (R/R CLL):
d) Histologically confirmed diagnosis of TP53^wt CLL according to iwCLL criteria;
e) Previously treated with at least 1 prior regimen according to
current guidelines;
f) Active disease meeting at least 1 of the iwCLL 2008 criteria for
requiring treatment;
3. ECOG performance status of 0 to 2;
4. Adequate hematologic function independent of growth factor support for at least 7 days with the exception of pegylated G-CSF and darbepoetin which require at least 14 days, defined as:
a) Absolute neutrophil count (ANC) ≥1,000/mm^3;
b) Platelet count ≥50,000/mm^3;
5. Adequate hepatic function within 28 days prior to first dose defined as:
a) Total bilirubin within normal limits (WNL); if total bilirubin is > upper limit of normal (ULN) then patients are eligible if the direct bilirubin is ≤2.0 x ULN;
b) Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤2.5 ULN;
6. Adequate renal function within 28 days prior to the first dose defined as an estimated creatinine clearance ≥30 mL/min by Cockcroft Gault;
7. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, both male and female subjects must continue to use contraception for 6 months after the last dose of study drug. Effective birth control for males includes either vasectomy or use of condoms. Effective birth control for females includes (a) combined estrogen- and progestogen-containing hormonal contraception (oral, intravaginal, transdermal); (b) intrauterine device combined with a barrier method; (c) intrauterine hormone-releasing system combined with a barrier method; (d) bilateral tubal occlusion or ligation; (e) vasectomized partner; and (f) sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Note: Marketed drugs administered concomitantly in this study may have
different contraception requirements, including required duration of
contraception use. The contraception requirements in the prescribing
information (PI) or summary of product characteristics (SmPC) must be
followed for all concomitant drugs administered in this study. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with a history of CNS involvement;
2. Any recent prior therapy meeting one or more of the following criter:
a) Concurrent anticancer treatment, such as chemotherapy, cytoreductive therapy, immune therapy, or cytokine therapy:
i) DLBCL: Within 14 days prior to the first dose of study treatment;
ii) CLL: Within 28 days prior to the first dose of study treatment;
b) Allogeneic stem cell transplant within the last 6 months, or active graft versus host disease following allogeneic transplant, or autologous stem cell transplant within 3 months prior to the first dose of study treatment;
c) Subjects who have received immunosuppressive therapy for graft-versus-host disease within 6 months prior to first dose of study treatment;
3. Subjects previously treated with MDM2 antagonist therapies;
4. Subjects previously treated with a BTK inhibitor;
5. Subjects with a history of bleeding diathesis or major hemorrhage within 6 months prior to first dose of study treatment;
6. History of stroke or intracranial hemorrhage within 6 months before first dose of study drug;
7. Uncontrolled intercurrent illness including but not limited to clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure, unstable angina pectoris; unstable ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements;
8. Grade 2 or higher QTc prolongation (>480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [v 5.0]);
9. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach; or extensive small bowel resection that is likely to affect absorption; symptomatic inflammatory bowel disease, or partial or complete bowel obstruction; or gastric restrictions and bariatric surgery, such as gastric bypass;#
10. Subjects with uncontrolled bacterial, fungal, parasitic, or viral infection. Subjects with acute bacterial infections requiring antibiotic use should not enroll until the infection is stable in the judgement of the treating physician; these subjects may be on antibiotics at time of enrollment;
11. Subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV);
12. Known history of HIV;
13. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, preprohormone) within 7 days of first dose of study drug;
14. Phase 1 only: Requires treatment with a strong and/or moderate CYP3A inhibitor/inducer within 7 days prior to first dose of study drug;
15. Phase 2 only: Requires treatment with a strong CYP3A inhibitor/inducer within 7 days prior to first dose of study drug;
16. Requires treatment with proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study provided the proton pump inhibitor is discontinued at least 5 days prior to first dose of study drug;
17. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma;
18. Subjects who have had major surgery within 28 days prior to the first dose;
19. Women who are pregnant or breastfeeding. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib:
1. Dose-limiting toxicities will be used to establish the MTD/MAD of KRT-232 in combination with acalabrutinib. The Safety Review Committee will determine the RP2D based on safety data of the combination of KRT-232 and acalabrutinib;
2. Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs.
Phase II:
1. The proportion of subjects with CR as assessed by investigators per the Lugano Classification;
2. The proportion of subjects with CR/CRi as assessed by investigators per iwCLL Response Criteria. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b:
1-2. Throughout the study
Phase II:
1-2. Throughout the study |
|
| E.5.2 | Secondary end point(s) |
Phase 1b:
1. KRT-232, acyl glucuronide metabolite (M1), acalabrutinib, and metabolite ACP-5862 pharmacokinetic (PK) parameters will be determined, including but not limited to:
• Maximum observed concentration (C^max)
• Minimum observed concentration (C^min)
• Area under the plasma concentration-time curve (AUC)
• Time of maximum plasma concentration
Phase II:
1. The proportion of subjects who achieve a partial response (PR) or better at any time point while on study, as assessed by Lugano Classification;
2. The proportion of subjects who achieve a PR or better at any time point while on study, as assessed by iwCLL Response Criteria;
3. Median DOR (Kaplan-Meier estimate) defined as the time from the first observation of response to disease progression or death;
4. The proportion of subject who achieve MRD negativity either in peripheral blood or bone marrow by flow cytometry and DNA sequencing;
5. Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs;
6. KRT-232, acyl glucuronide metabolite (M1), acalabrutinib, and metabolite ACP-5862 plasma concentrations will be monitored using sparse sampling. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1b:
1. Throughout the study
Phase II:
1-6. Throughout the study |
|
| 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 | No |
| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Czechia |
| France |
| Hungary |
| Italy |
| Korea, Republic of |
| Poland |
| Portugal |
| Switzerland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Last Patient Last Visit (LPLV) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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