A Phase 3 Randomise study to Assess the Efficacy and Safety of Ublituximab in Combination with TGR-1202 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)

• Register: EUCTR
• Last refreshed on: 9 January 2017
• Main ID: EUCTR2015-005758-36-ES
• Date of registration: 18/11/2016
• Prospective Registration: Yes
• Primary sponsor: TG Therapeutics
• Public title: A Phase 3 Randomise study to Assess the Efficacy and Safety of Ublituximab in Combination with TGR-1202 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)
• Scientific title: A Phase 3, Randomized Study to Assess the Efficacy and Safety of Ublituximab in Combination with TGR-1202 Compared to Obinutuzumab in Combination with Chlorambucil in Patients with Chronic Lymphocytic Leukemia (CLL)
• Date of first enrolment: 16/12/2016
• Target sample size: 450
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005758-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: clinical and statistical decisions are made in a treatment blinded manner. If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Obinutuzumab + Chlorambucil Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Canada, Czech Republic, Israel, Italy, Poland, Russian Federation, Spain, Ukraine, United States

Contacts

• Name: Peter Sportelli
• Affiliation: TG Therapeutics

• Name: Peter Sportelli
• Affiliation: TG Therapeutics

Key inclusion & exclusion criteria

Inclusion criteria:
1. B-cell CLL (treatment naïve or previously treated) that warrants treatment consistent with accepted IWCLL criteria for initiation of therapy. Any 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 / platelet count > 50,000.
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 patients 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 patients of child-bearing potential, and male partners must consent to use a medically acceptable method of contraception throughout the study period and for 30 days after the last dose of either study drug.
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 225
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 225

Exclusion criteria:
1. Patients 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 randomization (contact sponsor for < 21 day washout period requests)
a. Corticosteroid therapy started at least 7 days prior to 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 patients 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 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. Patients who have received prior therapy with obinutuzumab.Patients who are refractory to prior chlorambucil.(defined as disease progression while receiving or within 6 months of completion of a chlorambucil based regimen).
7. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal infections of skin or nails. NOTE: Patients may be receiving prophylactic antiviral or antibacterial therapies at investigator discretion. Use of anti-pneumocystis and antiviral prophylaxis is required for patients on TGR-1202 arms.
8. Live virus vaccines prior to or during obinutuzumab or ublituximab therapy.
9. 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 )
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.
10. 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.
11. Women who are pregnant or lactating.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Chronic Lymphocytic Leukemia
MedDRA version: 19.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Ublituximab
Product Code: TG-1101
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Ublituximab
Current Sponsor code: TG-1101
Other descriptive name: IgG1 immunoglobulins
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Product Name: TGR-1202
Product Code: TGR-1202
Pharmaceutical Form: Tablet
INN or Proposed INN: TGR-1202
Current Sponsor code: TGR-1202
Other descriptive name: (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl)-ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4 methylbenzenesulfonate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Gazyvaro 1,000 mg concentrate for solution for infusion.
Product Name: Gazyvaro 1,000 mg concentrate for solution for infusion.
Product Code: Obinutuzumab
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Obinutuzumab
CAS Number: 949142-50-1
Current Sponsor code: Obinutuzumab
Other descriptive name: Obinutuzumab
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: Chlorambucil 2 mg tablets
Product Name: Chlorambucil 2 mg tablets
Product Code: Chlorambucil
Pharmaceutical Form: Tablet
INN or Proposed INN: Chlorambucil
CAS Number: 305-03-3
Current Sponsor code: Chlorambucil
Other descriptive name: Chlorambucil
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Each primary end points will be evaluated every three months

Secondary Objective: 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 patients with CLL

Main Objective: 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

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 and PR rates.

Complete Response (CR) Rate
CR rate is defined as the proportion of patients who achieve a CR.

Minimal Residual Disease (MRD) Negativity Rate
MRD negativity rate is defined as the proportion of patients who are MRD negative.

Duration of response (DOR)
DOR is defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause.

Secondary Outcome(s)

Secondary end point(s): Efficacy

Timepoint(s) of evaluation of this end point: Efficacy will be evaluated every three months

Secondary ID(s)

UTX-TGR-304

Source(s) of Monetary Support

TG Therapeutics