A Study Of The Selective PKC-β Inhibitor MS- 553

Study Overview
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Brief Summary
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A Phase I/II Dose-Escalation and Expansion Study Of The Selective PKC-Β Inhibitor MS-553 In Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Official Title
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A Phase I/II Dose-Escalation and Expansion Study of the Selective PKC-β Inhibitor MS-553 in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Conditions
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Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Aggressive Lymphoma

Intervention / Treatment
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* Drug: MS-553
* Drug: MS-553
* Drug: acalabrutinib
* Drug: venetoclax
* Drug: Rituximab
* Drug: obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for inclusion in the primary escalation and expansion cohort 1 in this study, patients must meet all of the following criteria: Age 18 years or older Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL): History of histologically documented CLL or SLL that meets IWCLL diagnostic criteria according to the 2008 guidelines, and Indication for treatment as defined by the 2008 IWCLL guidelines, or the need for disease reduction prior to allogeneic transplantation Exclusion Criteria: Patients who meet any of the following criteria are not eligible for the primary escalation and expansion cohorts of this study: Current or past transformation of CLL/SLL to prolymphocytic leukemia (PLL), non-Hodgkin lymphoma, or Hodgkin lymphoma aggressive lymphoma outlined in the inclusion criteria for the optional cohort. Active and uncontrolled autoimmune cytopenia(s) Any of the following prior therapies within 14 days prior to cycle 1, day 1: Major surgery Corticosteroids greater than 20 mg / day prednisone (or equivalent), unless used by inhalation or topical route, or unless necessary for premedication before iodinated contrast dye, or for autoimmune hemolytic anemia Cytotoxic chemotherapy or biologic therapy, excepting BCR pathway kinase inhibitors for which no wash out is required (but must be stopped before cycle 1 day 1)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: a limited 3+3 phase 1 dose escalation study with expansion cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Escalation Cohort A1 (MS-553 Monotherapy)<br>R/R CLL/SLL patients | Drug: MS-553<br>* Oral, multiple dose levels<br>|
| Experimental: Phase II Expansion Cohort A2 (MS-553 Monotherapy)<br>R/R CLL/SLL patients | Drug: MS-553<br>* Oral recommended phase 2 dose of MS-553<br>|
| Experimental: Phase II Expansion Cohort A3 (MS-553 Monotherapy)<br>patients with aggressive lymphoma | Drug: MS-553<br>* Oral recommended phase 2 dose of MS-553<br>|
| Experimental: Phase I Combination Dose Escalation Cohort B1<br>BTK inhibitor naïve CLL/SLL patients | Drug: MS-553<br>* Oral, multiple dose levels<br>Drug: acalabrutinib<br>* Oral<br>|
| Experimental: Phase II Expansion Cohort B2<br>BTK inhibitor naïve CLL/SLL patients | Drug: MS-553<br>* Oral recommended phase 2 dose of MS-553<br>Drug: acalabrutinib<br>* Oral<br>|
| Experimental: Phase II Expansion Cohort B3<br>BTK inhibitor naïve CLL/SLL patients with certain gene mutations | Drug: MS-553<br>* Oral recommended phase 2 dose of MS-553<br>Drug: acalabrutinib<br>* Oral<br>|
| Experimental: Phase I Combination Dose Escalation Cohort C1<br>Bcl-2 inhibitor naïve CLL/SLL patients | Drug: MS-553<br>* Oral, multiple dose levels<br>Drug: venetoclax<br>* Oral<br>* Other names: Venclyxto;Drug: Rituximab<br>* IV<br>* Other names: MabThera;Drug: obinutuzumab<br>* IV<br>* Other names: Gazyva;|
| Experimental: Experimental: Phase II Expansion Cohort C2<br>Bcl-2 inhibitor naïve CLL/SLL patients | Drug: MS-553<br>* Oral recommended phase 2 dose of MS-553<br>Drug: venetoclax<br>* Oral<br>* Other names: Venclyxto;Drug: Rituximab<br>* IV<br>* Other names: MabThera;Drug: obinutuzumab<br>* IV<br>* Other names: Gazyva;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective of this study is to evaluate the safety of MS-553 in patients with CLL/SLL whose disease relapsed after or was refractory to at least one prior therapy. | The primary endpoint of this study is the incidence rate of dose-limiting toxicities and treatment-emergent adverse events requiring study drug discontinuation | Assessments for DLT and TEAE will occur during cycle 1. The primary endpoint will be the rate of DLT and TEAE requiring study drug discontinuation in the first 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the clinical activity (i.e. the overall response rate (ORR) of MS-553 in patients with CLL/SLL whose disease relapsed after or was refractory to at least one prior therapy. | This will be assessed according to the International Workshop on Chronic Lymphocytic Leukemia Response Criteria with modifications for treatment-related lymphocytosis. | Screening, post cycle 3 and 6 cycles (each cycle is 28 days) |