| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| CLL is a type of cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow. The cancer cells start in the bone marrow but then go into the blood. |
|
| 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 | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To establish that the combination of ublituximab + TGR-1202 is superior to the combination of obinutuzumab + chlorambucil as measured by Progression-Free Survival (PFS) in patients with CLL |
|
| E.2.2 | Secondary objectives of the trial |
To establish that the combination of ublituximab + TGR-1202 provides clinical benefit over both ublituximab alone and TGR-1202 alone
To evaluate and compare the combination of ublituximab + TGR-1202 to the combination of obinutuzumab + chlorambucil with respect to overall response rate in subjects with CLL
To assess safety, tolerability and other efficacy outcomes.
To determine the pharmacokinetics and any potential drug-drug interactions of ublituximab and TGR-1202 in combination. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. B-cell CLL (treatment naïve or previously treated) that warrants treatment consistent with accepted IWCLL criteria for initiation of therapy. Any one of the following conditions constitute CLL that warrants treatment:
a. Evidence of progressive marrow failure as manifested by the onset or worsening of anemia and/or thrombocytopenia, or
b. Massive (i.e., lower edge of spleen ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or
c. Massive (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy, or
d. Progressive lymphocytosis in the absence of infection, with an increase in blood absolute lymphocyte count (ALC) >50% over a 2-month period or lymphocyte doubling time of <6 months (as long as initial ALC was ≥30,000/L), or
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, or
f. Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs occurring in the absence of evidence of infection:
i. Unintentional weight loss of ≥10% within the previous 6 months, or
ii. Significant fatigue (≥ Grade 2), or
iii. Fevers >100.5°F or 38.0°C for ≥2 weeks, or
iv. Night sweats for >1 month.
2. Adequate organ system function, defined as follows:
a. Absolute neutrophil count (ANC) > 1,000 /mm3 (microlitre)/ platelet count > 50,000/mm3 (microlitre).
b. Total bilirubin ≤1.5 times the upper limit of normal (ULN)
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if no liver involvement or ≤5 x the ULN if known liver involvement
d. Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault formula)
3. Presence of measurable lymphadenopathy, defined as the presence of > 1 nodal lesion that measures > 2.0 cm in a the longest diameter (LD) and > 1.0 cm in the longest perpendicular diameter (LPD) as assessed by computed tomography (CT) or magnetic resonance imaging (MRI)
4. ECOG performance status ≤ 2
5. Male or female ≥ 18 years of age
6. Ability to swallow and retain oral medication
7. Female subjects who are not of child-bearing potential (see Appendix B- Contraceptive Guidelines and Pregnancy), and female patients of child-bearing potential who have a negative serum pregnancy test within 3 days prior to Cycle 1, Day 1. Female subjects of child-bearing potential, and male partners must consent to use a medically acceptable method of contraception throughout the study period and for 4 months after the last dose of ublituximab or TGR-1202, or 18 months after the last dose of obinutuzumab or at least 4 weeks after the last dose of chlorambucil.
8. Willingness and ability to comply with trial and follow-up procedures, and give written informed consent |
|
| E.4 | Principal exclusion criteria |
1. Subjects receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) or any investigational drug within 21 days of cycle 1/day 1 (contact sponsor for < 21 day washout period requests)
a. Corticosteroid therapy started at least 7 days prior to cycle 1/ day 1 study entry (prednisone ≤10 mg daily or equivalent) is allowed as clinically warranted. Topical or inhaled corticosteroids are permitted.
2. Autologous hematologic stem cell transplant within 3 months of study entry. Prior Allogeneic hematologic stem cell transplant is excluded.
3. Evidence of chronic active Hepatitis B (HBV, not including subjects with prior hepatitis B vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C infection (HCV), cytomegalovirus (CMV), or known history of HIV. If HBc antibody, HCV antibody or CMV IgM is positive the subject must be evaluated for the presence of HBV, HCV, or CMV by DNA (PCR).
4. Known histological transformation from CLL to an aggressive lymphoma (i.e. Richter’s transformation)
5. Prior exposure to idelalisib (CAL-101), duvelisib (IPI-145), ACP-319, or any drug that specifically inhibits phosphoinositide-3-kinase (PI3K)
6. Subjects who have received prior therapy with obinutuzumab. Subjects who are refractory to prior chlorambucil.
7. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infections of skin or nails. NOTE: Subjects may be receiving prophylactic antiviral or antibacterial therapies at investigator discretion. Use of anti-pneumocystis and antiviral prophylaxis is encouragedis required for subjects on TGR-1202 arms.
8. Live virus vaccines within 4 weeks prior to or during obinutuzumab or ublituximab therapy.
9. History of anaphylaxis (excluding infusion related reactions) in association with previous anti-CD20 administration.
10. Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
a. Symptomatic, or history of documented congestive heart failure (NY Heart Association functional classification III-IV [Appendix C – NYHA Classifications Appendix C)
b. Myocardial infarction within 6 months of randomization
c. QTcF >470 msec
d. Angina not well-controlled by medication
e. Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac/vascular stenting within 6 months of randomization.
11. Malignancy within 3 years of study enrollment except for adequately treated basal, squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, localized prostate cancer and PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the most recent one being within 4 weeks of study entry.
12. Women who are pregnant or lactating. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS)
PFS is defined as the interval from randomization to the earlier of the first documentation of definitive disease progression or death from any cause.
Definitive disease progression based on standard criteria (Hallek et al. 2008) and occurring for any reason (i.e., increasing lymphadenopathy, organomegaly or bone marrow involvement; decreasing platelet count, hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other than lymphocytosis.
Overall response rate (ORR)
ORR is defined as sum of CR, CRi, PR and nPR rates
Complete Response (CR) Rate
CR rate is defined as the proportion of subjects who achieve a CR or CRi.
Minimal Residual Disease (MRD) Negativity Rate
MRD negativity rate is defined as the proportion of subjects who are MRD negative.
Duration of response (DOR)
DOR is defined as the interval from the first documentation of CR, CRi, PR or nPR to the earlier of the first documentation of definitive disease progression or death from any cause.
Overall Survival (OS)
OS is defined as the interval from randomization to death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Each primary end points will be evaluated every three months |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Efficacy will be evaluated every three months |
|
| 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 | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Obinutuzumab + Chlorambucil |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 33 |
| 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 |
| Israel |
| Italy |
| Poland |
| Russian Federation |
| Spain |
| United States |
|
| 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
|
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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