A Phase 3 Randomise study to Assess the Efficacy and Safety of Ublituximab in Combination with TGR-1202 (Umbralisib) Compared to Obinutuzumab in Combination with Chlorambucil in Patients with Chronic Lymphocytic Leukemia (CLL) (A Chronic lymphocytic leukemia (CLL) is a type of cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow. The cancer (leukemia) cells start in the bone marrow but then go into the blood)

Phase 1

• Conditions: Chronic Lymphocytic Leukemia; MedDRA version: 21.0Level: LLTClassification code 10008976Term: Chronic lymphocytic leukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-005758-36-GB
• Lead Sponsor: TG Therapeutics

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2016-12-06
• Last Update Posted: 4 May 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 450

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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 6
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 6

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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified