| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Male or female adult patients with an advanced B-Lymphoid malignancies that have relapsed/progressed after appropriate prior therapy and have resistance and/or mutations that may respond to subsequent BTK inhibition using SNS-062. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Male or female adult patients with an advanced B-Lymphoid malignancies who have resistance and/or mutations that may respond to subsequent BTK inhibition using SNS-062. |
|
| 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10026798 |
| E.1.2 | Term | Mantle cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10047802 |
| E.1.2 | Term | Waldenstrom's macroglobulinaemias |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008948 |
| E.1.2 | Term | Chronic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 MTD and/or RD of SNS-062
Phase 2: To evaluate the objective response rate (ORR) by cohort in subjects receiving SNS-062
|
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b:
- To characterize the safety profile of SNS-062
- To characterize the PK profile of SNS-062
- To characterize the antitumor activity of SNS-062
- To assess the preliminary effect of SNS-062 on the QTc interval
Phase 2:
- To further characterize additional antitumor activity by cohort in subjects receiving SNS-062
- To characterize the safety profile of SNS-062
- To characterize the plasma PK profile of SNS-062
- To assess the preliminary effect of SNS-062 on the QTc interval
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Men and women of age ≥18 years
2)Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2
3)Histologically confirmed malignancy with relapsed/refractory disease:
a)After ≥2 lines of standard systemic therapy including prior BTK inhibitor therapy:
i)CLL
ii)LPL/WM
iii)MCL
b)After ≥2 lines of standard systemic therapy:
i)DLBCL-ABC
ii)FL
4)For subjects in:
a)Phase 1b and 2:
Availability of a peripheral blood sample or a bone marrow aspirate or a lymph node biopsy obtained during the screening period for evaluation of predictive/prognostic disease parameters and to determine if there is a functional BTK C481 mutation (ie BTK C481S) or a resistance or gain of function mutation(s) (ie, PLCγ2 R665W)
b)Phase 2 only:
i)For CLL: the presence of a functional BTK C481 mutation (ie, ≥1% BTK C481 mutation), and absence of a resistance or gain of function mutation (ie, PLCγ2 R665W) or
ii)For CLL: absence of a functional BTK C481mutation alone (<1% BTK C481 mutation)
iii)For LPL/WM: no mutation requirement
iv)For MCL: no mutation requirement
5)Presence of measurable disease:
a)For subjects with small lymphocytic lymphoma (SLL), MCL, DLBCL-ABC, FL: presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy
b)For subjects with LPL/WM: presence of serum monoclonal immunoglobulin protein (M-protein) ≥1 g/dL (but subject does not have symptomatic hyperviscosity syndrome [HVS] and does not require immediate plasmapheresis for control of HVS)
6)Current medical need for therapy of the B-lymphoid malignancy due to disease-related symptoms, lymphadenopathy, organomegaly, extranodal organ involvement, or PD
7)An interval of ≥3 half-lives (unless the last therapy was an antibody where 1 half-life or 14 days, whichever is shorter, is acceptable with demonstrated progression by standard guidelines) from the completion of all previous antitumor therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) to the start of study therapy
8)All acute toxic effects of any prior antitumor therapy resolved to Grade 1 before the start of study therapy (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade ≤2 permitted], or selected laboratory parameters [Grade ≤2 permitted with exceptions noted below])
9)Adequate thyroid function (TSH, T3, T4) with or without thyroid replacement (Grade ≤2)
10)Adequate hepatic profile:
a)Serum alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN) (Grade ≤1)
b)Serum aspartate aminotransferase (AST) ≤3 × ULN (Grade ≤1)
c)Serum alkaline phosphatase (ALP) ≤2.5 × ULN (Grade ≤1)
d)Serum bilirubin ≤1.5 × ULN (Grade ≤1) except for subjects with Gilbert’s disease
11)Adequate renal function:
a)Estimated creatinine clearance (eClCR) >45 mL/minute (with eClCR to be calculated by the Cockcroft-Gault formula [Appendix 3]),
OR
b)Measured creatinine clearance >45 mL/minute (assessed with a 24 hour urine collection)
12)Adequate pancreatic profile:
a)Serum amylase ≤1.5 × ULN (Grade ≤1)
b)Serum lipase ≤1.5 × ULN (Grade ≤1)
13)Haematology Requirements:
a)Platelet count ≥50 × 109/L (Grade ≤2) maintained for ≥7 days after any prior transfusion
b)For subjects without bone marrow involvement:
i)Absolute neutrophil count (ANC) ≥0.750 × 109/L
ii)Hemoglobin (Hb) ≥8.0 g/dL, stable for ≥7 days
c)For subjects with bone marrow involvement:
i)Absolute neutrophil count (ANC) ≥500 cells/µL
14)Adequate coagulation profile:
a)Prothrombin time (PT) ≤1.5 × ULN (Grade ≤1)
b)Activated partial thromboplastin time (aPTT) ≤1.5 × ULN (Grade ≤1)
15)Negative antiviral serology:
a)Negative human immunodeficiency virus (HIV) antibody
b)Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) antibody or undetectable hepatitis B virus (HBV) DNA by quantitative polymerase chain reaction (PCR) testing
c)Negative hepatitis C virus (HCV) antibody or negative HCV RNA by quantitative PCR
|
|
| E.4 | Principal exclusion criteria |
1)Transformed disease at time of screening (eg, Richter’s transformation or of blastoid variant MCL)
2)Known central nervous system malignancy
Note:Central nervous system imaging is only required in subjects with suspected central nervous system malignancy.
3)History of another malignancy except for the following adequately treated:
a)Local basal cell or squamous cell carcinoma of the skin
b)Carcinoma in situ of the cervix or breast
c)Papillary, noninvasive bladder cancer
d)Prostate cancer Stage 1 and 2 for which observation is clinically indicated with stable prostate-specific antigen (PSA) for 6 months
e)Other Stage 1 or 2 cancers currently in complete remission
f)Any other cancer that has been in complete remission for 2 years or surgically cured
4)Significant cardiovascular disease
a)Myocardial infarction, arterial thromboembolism, or cerebrovascular thromboembolism within 6 months prior to start of study therapy
b)Symptomatic angina
c)Symptomatic peripheral vascular disease
d)New York Heart Association Class ≥3 congestive heart failure
e)Uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite antihypertensive therapy
f)Uncontrolled arrhythmia
5)Significant screening ECG abnormalities:
a)Left bundle branch block
b)2nd or 3rd-degree Atrioventricular block Type 2
c)Grade ≥2 bradycardia
d)QTc by either Bazett or Fridericia method (QTcB or QTcF) >450 msec (for men) or >470 msec (for women)
6)Gastrointestinal disease (eg, gastric or intestinal bypass surgery, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic diarrheal illness, bowel obstruction) that might interfere with drug absorption or with interpretation of gastrointestinal AEs
7)Ongoing risk for bleeding due to any of the following:
a)Bleeding diathesis
b)Known platelet function disorder
c)Uncontrolled peptic ulcer disease
d)Oral anticoagulation (eg, warfarin, apixaban, rivaroxaban, dabigatran etexilate)
e)Heparin, low-molecular-weight heparin or heparin fractions (eg, enoxaparin, dalteparin, fondaparinux)
Note:Use of heparin or thrombolytic agents for local maintenance or clearance of a central venous catheter is permitted.
8)Evidence of an uncontrolled systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) at the time of start of study therapy
Note:Subjects with localized fungal infections of skin or nails are eligible.
9)Demonstrated intolerance to a BTK inhibitor as evidenced by discontinuation of BTK inhibitor due to AE or required dose reduction due to AE
10)Transplant
a)Evidence of ongoing graft-versus-host disease after prior stem cell transplant
b)Prior solid organ transplant
11)Pregnancy or breastfeeding
12)Major surgery within 4 weeks before the start of study therapy
13)Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids except as noted
Note:At screening, subjects may be using systemic corticosteroids (at physiologic doses of ≤10 mg/day of prednisone or equivalent) or topical or inhaled corticosteroids.
14)Use of a moderate or strong inhibitor or inducer of CYP3A4 within 7 days prior to the start of study therapy or expected requirement for use during study therapy
15)Use of substrates of CYP2C8, CYP3A4, CYP2B6, CYP2C9 and CYP2D6 with narrow therapeutic index within 7 days prior to the start of study therapy or expected requirement for use during study therapy
16)Any illness, medical condition, organ system dysfunction, or social situation, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with a subject’s ability to sign informed consent, adversely affect the subject’s ability to cooperate and participate in the study, or compromise the interpretation of study results |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b: MTD and/or RD within the tested SNS-062 dose range
Phase 2: ORR by cohort as evaluated by standard response and progression criteria for each tumor type |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Phase 1b:
- Type, frequency, severity, and relatedness to study drug of treatment emergent adverse events (TEAEs), laboratory abnormalities, or electrocardiogram (ECG) findings
- SNS-062 plasma PK parameters (including area under the plasma concentration-time curve [AUC], maximum concentration [Cmax], time of maximum concentration [Tmax], half-life [t1/2], apparent volume of distribution [Vd/F], terminal elimination rate constant [λz], and apparent clearance [Cl/F])
- ORR, time to response (TTR), duration of response (DOR), progression-free-survival (PFS), as evaluated by standard response and progression criteria for each tumor type
- QTc interval parameters, including changes from baseline and absolute increases in QTc interval
Phase 2b
- TTR, DOR, PFS, and OS by cohort as evaluate and progression criteria for each tumor type
- Type, frequency, severity, and relatedness to study drug of TEAEs, laboratory abnormalities, or ECG findings
- SNS 062 plasma PK parameters (including AUC, Cmax, Tmax, t1/2,Vd/FF, λz, and Cl/F)
- QTc interval parameters, including changes from baseline and absolute increases in QTc interval
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Type, frequency, severity, and relatedness to study drug of TEAEs, laboratory abnormalities, or ECG findings: thoughout the trial
- SNS 062 plasma PK parameters: Cycle 1 days 1,2,8,15, Cycle 2 Day 1
- ORR, TTR, DOR, PFS, and OS : throughout the trial
- QTc : Cycle 1 days 1, 2, 8, 15, Cycle 2 Day 1 to Cycle X day 1, EoT |
|
| 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 | Yes |
| 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 | Yes |
| 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 |
| Dose escalation and Dose expansion |
|
| 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.8.3 |
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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| France |
| Germany |
| United Kingdom |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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