E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Lymphocytic Leukemia (CLL) |
|
E.1.1.1 | Medical condition in easily understood language |
Chronic Lymphocytic Leukemia (CLL) |
|
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 | PT |
E.1.2 | Classification code | 10008958 |
E.1.2 | Term | Chronic lymphocytic leukaemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 |
To evaluate the effect of the addition of GS-1101 to rituximab on PFS in subjects with
previously treated CLL |
|
E.2.2 | Secondary objectives of the trial |
• To determine the effect of the addition of GS-1101 to rituximab on the onset, magnitude,
and duration of tumor control
• To assess the effect of the addition of GS-1101 to rituximab on measures of subject wellbeing,
including OS, HRQL, and performance status
• To assess the effects of the addition of GS-1101 to rituximab on disease-associated
biomarkers and to evaluate potential mechanisms of resistance to GS-1101
• To characterize exposure to study treatment as determined by treatment administration
with each of the therapeutic agents, evaluation of GS-1101 plasma concentrations over
time
• To describe the safety profile observed with the addition of GS-1101 to rituximab
• To estimate health resource utilization associated with the addition of GS-1101 to
rituximab |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Male or female ≥18 years of age.
2) Diagnosis of B-cell CLL, with diagnosis established according to IWCLL criteria
[Hallek 2008] and documented within medical records.
3) CLL that warrants treatment (consistent with accepted criteria for initiation of therapy
[Hallek 2008]).
4) Presence of radiographically measurable lymphadenopathy (defined as the presence of
≥1 nodal lesion that measures ≥2.0 cm in the longest dimension [LD] and ≥1.0 cm in the
longest perpendicular dimension [LPD] as assessed by CT or MRI).
5) Prior treatment for CLL
6) In a subject whose last prior therapy contained an anti-CD20 antibody (eg, rituximab,
ofatumumab, GA-101), evidence of disease improvement during that therapy or
documentation of CLL progression ≥6 months after completion of that therapy. Note:
Subjects who did not receive a therapeutic anti-CD20 antibody (eg, rituximab,
ofatumumab, GA-101) as a component of the last prior therapy need not have
experienced disease improvement or may have relapsed <6 months from the completion
of the prior regimen.
7) Documentation of CLL progression <24 months since the completion of the last prior
therapy for CLL.
8) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy,
systemic corticosteroids, or investigational therapy) for the treatment of CLL ≥3 weeks
before randomization.
9) All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before
randomization (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity
[Grade 1 or 2 permitted], or bone marrow parameters [Grades 1, 2, 3, or 4 permitted).
10) Karnofsky performance score of ≥40.
11) Appropriate for non-cytotoxic-containing therapy.
12) Required baseline laboratory data (within 4 weeks prior to randomization) as shown in
the table below. Note: Confirmation should be considered for out-of-range values to
determine if the abnormality is real or artifactual. Values should be obtained within
the screening period and should generally be the most recent measurement obtained.
Subjects with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or
prior therapy may enroll.
13) For female subjects of childbearing potential, willingness to abstain from heterosexual
intercourse or use a protocol-recommended method of contraception from the screening
visit (Visit 1) throughout the study treatment period and for 30 days following the last
dose of study drug. Note: A female subject is considered to be of childbearing potential
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy,
has medically documented ovarian failure (with serum estradiol and folliclestimulating
hormone [FSH] levels within the institutional postmenopausal range and a
negative serum or urine βHCG), or is menopausal (age ≥55 years with amenorrhea for
≥6 months). See Section 5.6.4 for information regarding recommendations for
contraception.
14) For male subjects of childbearing potential and having intercourse with females of
childbearing potential, willingness to abstain from heterosexual intercourse or use a
protocol-recommended method contraception from the randomization visit (Visit 2)
throughout the study treatment period and for 90 days following the last dose of study
drug and to refrain from sperm donation from randomization (Visit 2) throughout the
study treatment period and for 90 days following the last dose of study drug. Note: A
male subject is considered able to father a child unless he has had a bilateral
vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing
testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH)
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin
pamoate [Trelstar®]).
15) In the judgment of the investigator, participation in the protocol offers an acceptable
benefit-to-risk ratio when considering current CLL disease status, medical condition, and
the potential benefits and risks of alternative treatments for CLL.
16) Willingness to comply with scheduled visits, drug administration plan, imaging studies,
laboratory tests, other study procedures, and study restrictions. Note: Psychological,
social, familial, or geographical factors that might preclude adequate study
participation should be considered.
17) Evidence of a personally signed informed consent indicating that the subject is aware of
the neoplastic nature of the disease and has been informed of the procedures to be
followed, the experimental nature of the therapy, alternatives, potential benefits, possible
side effects, potential risks and discomforts, and other pertinent aspects of study
participation. |
|
E.4 | Principal exclusion criteria |
1) Known histological transformation from CLL to an aggressive lymphoma (ie, Richter
transformation). Note: Biopsy documentation of the absence or presence of
transformation is not required.
2) Presence of intermediate- or high-grade myelodysplastic syndrome (ie, subjects are
excluded who have ≥5 bone marrow blasts; karotypic abnormalities other than normal,
Y deletion, 5q deletion, or 20q deletion; or ≥2 lineages of cytopenias) [Greenberg 1997].
3) History of a non-CLL malignancy except for the following: adequately treated local basal
cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial
bladder cancer, asymptomatic prostate cancer without known metastatic disease and with
no requirement for therapy or requiring only hormonal therapy and with normal
prostate-specific antigen for ≥1 year prior to randomization, other adequately treated
Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in
complete remission for ≥5 years.
4) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of initiation
of randomization (Visit 2). Note: Subjects with localized fungal infections of skin or
nails are eligible. Subjects may be receiving prophylactic antiviral or antibacterial
therapies at the discretion of the investigator; anti-pneumocystis prophylaxis is
encouraged. For subjects who are at substantial risk of an infection (eg, influenza) that
may be prevented by immunization, consideration should be given to providing the
vaccine prior to initiation of protocol therapy.
5) Known history of drug-induced liver injury, chronic active hepatitis C (HCV), chronic
active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary
biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of
the liver, or portal hypertension.
6) Known history of drug-induced pneumonitis.
7) Ongoing inflammatory bowel disease.
8) Ongoing alcohol or drug addiction.
9) Pregnancy or breastfeeding.
10) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
11) Ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of
CLL. Note: Subjects may use topical, enteric, or inhaled corticosteroids as therapy for
comorbid conditions and systemic steroids for autoimmune anemia and/or
thrombocytopenia. Ongoing use of low-dose systemic corticosteroids (≤5 mg/day of
methylprednisolone or equivalent) for rheumatologic conditions is permitted. During
study participation, subjects may receive systemic or other corticosteroids as
pretreatment for rituximab infusions or as needed for treatment-emergent comorbid
conditions.
12) Prior therapy with any inhibitor of Bruton tyrosine kinase (BTK), Janus kinase (JAK),
mammalian target of rapamycin (mTOR), phosphatidylinositol 3 kinase (PI3K)
(including GS 1101), or spleen tyrosine kinase (Syk).
13) History of anaphylaxis in association with previous administration of monoclonal
antibodies
14) Concurrent participation in another therapeutic clinical trial.
15) Prior or ongoing clinically significant illness, medical condition, surgical history,
physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the
investigator’s opinion, could adversely affect the safety of the subject or impair the
assessment of study results. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) – 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 is CLL progression based on standard criteria and
occurring for any reason (ie, increasing lymphadenopathy, organomegaly or bone marrow
involvement; decreasing platelet count, hemoglobin, or neutrophil count; or worsening of
disease-related symptoms) other than lymphocytosis alone |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• Overall response rate (ORR) – defined as the proportion of subjects who achieve a
complete response (CR) or partial response (PR)
• Time to response (TTR) – defined as the interval from randomization to the first
documentation of CR or PR
• Duration of response (DOR) – 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
• Time to treatment failure (TTF) – defined as the interval from randomization to the
earliest of the first documentation of definitive disease progression, the permanent
cessation of study drug (GS-1101/placebo) due to an adverse event, or death from any
cause
Percent change in lymph node area – defined as the percent change from baseline in the
sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes
• Lymph node response rate – defined as the proportion of subjects who achieve a ≥50%
decrease in the SPD of index lymph nodes
• Splenomegaly response rate – defined as the proportion of subjects with baseline
splenomegaly who achieve an on-study normalization or a decrease by ≥50% from
baseline in the pretreatment enlargement of the splenic longest vertical dimension (LVD)
(by imaging) or in the pretreatment enlargement of the splenic LVD below the left costal
margin (by palpation)
• Hepatomegaly response rate – defined as the proportion of subjects with baseline
hepatomegaly who achieve an on-study normalization or a decrease by ≥50% from
baseline in the pretreatment enlargement of the hepatic LVD (by imaging) or in the
pretreatment enlargement of the hepatic LVD at the right midclavicular line (by
percussion)
• Platelet response rate – defined as the proportion of subjects with baseline
thrombocytopenia (platelet count <100 x 109/L) who achieve an on-study platelet count
≥100 x 109/L or demonstrate a ≥50% increase in platelet count from baseline
• Hemoglobin response rate – defined as the proportion of subjects with baseline anemia
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin ≥110 g/L
(11.0 g/dL) or demonstrate a ≥50% increase in hemoglobin from baseline
• Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia
(absolute neutrophil count [ANC] <1 x 109/L) who achieve an ANC ≥1 x 109/L or
demonstrate a ≥50% increase in ANC from baseline |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | Yes |
E.8.1.5 | Parallel group | Yes |
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) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 21 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 |
Italy |
United Kingdom |
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
|
It is expected that the final analysis of the study will take place after a minimum of
12 months of follow-up. The analysis will be conducted after the 119th event (definitive CLL
progression or death) or 18 months from the time the last subject is enrolled (whichever
occurs first). Once outstanding data queries have been resolved, the database will be locked,
the blind will be broken, and the final analysis of the study will be performed. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |