| 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 | 16.0 |
| 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 | Yes |
| 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 ofatumumab on progression-free survival (PFS) in subjects with previously treated chronic lymphocytic leukemia (CLL) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of the addition of GS-1101 to ofatumumab on the onset, magnitude, and duration of tumor control
• To assess the effect of the addition of GS-1101 to ofatumumab on measures of subject well-being, including overall survival (OS), health-related quality of life (HRQL) and performance status
• To assess the effects of the addition of GS-1101 to ofatumumab 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 and evaluation of GS-1101 plasma concentrations over time
• To describe the safety profile observed with the addition of GS-1101 to ofatumumab
• To estimate health resource utilization associated with the addition of GS-1101 to ofatumumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:
1) Male or female ≥18 years of age.
2) Diagnosis of B-cell CLL, with diagnosis established according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and documented within medical records.
3) CLL 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 (ie, lower edge of spleen ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly, or
c) Massive (ie, ≥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.
4) Presence of 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 computed tomography [CT] or magnetic resonance imaging [MRI]).
5) Prior treatment for CLL comprising therapy with either of the following types of drugs given alone or in combination:
a) A purine analog (eg, fludarabine, pentostatin, cladribine) administered for ≥2 cycles of treatment
b) Bendamustine administered for ≥2 cycles of treatment
6) Documentation of CLL progression <24 months since the completion of the last prior therapy for CLL.
7) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of CLL ≥6 weeks before randomization. Note: Subjects
may be receiving corticosteroids to manage CLL manifestations.
8) 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 [any of Grade 1, 2, 3, or 4 permitted]).
9) Karnofsky performance score of ≥60.
10) Required baseline laboratory data (within 4 weeks prior to randomization) as shown in the table located in the study protocol synopsis.
11) For female subjects of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocolrecommended method of contraception from the screening visit (Visit 1) throughout the study treatment period, and to 30 days from the last dose of study drug or 12 months from the last dose of ofatumumab (whichever is later).
12) For male subjects of childbearing potential having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended
method of 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.
13) 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.
14) Willingness and ability 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.
15) 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 |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
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) Known 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 due to myelodysplasia).
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 ≥2 years.
4) Known hypersensitivity or intolerance to any of the active substances or excipients in the formulations for either GS-1101 or ofatumumab
5) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time 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.
6) Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
7) Ongoing drug-induced pneumonitis.
8) Ongoing inflammatory bowel disease.
9) Ongoing alcohol or drug addiction.
10) Pregnancy or breastfeeding.
11) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
12) Ongoing immunosuppressive therapy other than corticosteroids. Note: Subjects may use topical, enteric, inhaled, or systemic corticosteroids as therapy for manifestations of CLL, comorbid conditions, or autoimmune anemia and/or thrombocytopenia. During study participation, subjects may receive systemic or other corticosteroids as pretreatment for ofatumumab infusions or as needed for treatment-emergent comorbid conditions.
13) In a subject with a history of prior ofatumumab therapy, the time from the last dose of ofatumumab to documented CLL progression is <6 months.
14) History of prior therapy with any inhibitor of AKT, Bruton tyrosine kinase (BTK), Janus kinase (JAK), mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K) (including GS-1101), or spleen tyrosine kinase (SYK).
15) Concurrent participation in another therapeutic clinical trial.
16) 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 |
Clinic/laboratory visits will occur weekly for Weeks 1 through 8, every 4 weeks at Weeks 12, 16, 20, and 24, and every 6 weeks between Weeks 24 and 48. Subjects continuing on study treatment past Week 48 will have clinic visits every 12 weeks. Subjects will be assessed for safety at each visit. Subjects will be assessed for CLL disease status by physical and laboratory examinations at each visit and by CT or MRI at Weeks 8, 16, 24, 36, 48 and every 12 weeks thereafter through Week 96. For follow-up visits after Week 96, CT or MRI is only required at the end-of-therapy visit.
The proportion of subjects who are progression-free at 24 and 48 weeks from randomization will be presented. |
|
| E.5.2 | Secondary end point(s) |
Tumor Control
• 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 GS-1101 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 from baseline 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 vertical splenic dimension
• 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)
• ALC response rate – defined as the proportion of subjects with baseline lymphocytosis (ALC≥4 x 109/L) who achieve an onstudy ALC <4 x 109/L or demonstrate a ≥50% decrease in ALC from baseline
• 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
Patient Well-Being
• Overall survival (OS) – defined as the interval from randomization to death from any cause
• Change in HRQL domain and symptom scores based on the Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
• Changes in Karnofsky performance status – defined as the change from baseline in the performance status and the time to definitive performance status improvement or worsening; time to definitive performance status improvement (better than baseline) is the interval from randomization to the first timepoint when the performance status is consistently better than at baseline (including that timepoint as well as all the subsequent timepoints) in a subject whose last performance status score is better than at baseline; and time to definitive performance status worsening (worse than baseline) is the interval from randomization until the earliest of death or the first timepoint when the performance status is consistently worse than at baseline (including that timepoint as well as all the subsequent timepoints) in a subject whose last performance status score is worse than at baseline
Pharmacodynamic Markers of Drug Activity and Resistance
• Changes from baseline in PI3K/Akt/mTOR pathway activation as a measure of PI3Kδ pathway activity
• Changes from baseline in the plasma concentrations of disease-associated chemokines and cytokines
Exposure
• Study drug administration as assessed by prescribing records and compliance as assessed by quantification of used and unused drug
• Trough (pre-dose) and peak (1.5-hour samples) of GS-1101 plasma concentrations as assessed by a validated bioanalytical method
Safety
• Overall safety profile of each study treatment regimen characterized by the type, frequency, severity, timing of onset, duration, and relationship to study therapy of any adverse events or abnormalities of laboratory tests; serious adverse events; or adverse events leading to discontinuation of study treatment
Pharmacoeconomics
• Change in health status – defined as the change from baseline in overall health and single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility measure
• Health resource measures, including resource utilization, total costs, and measures of cost per unit of benefit (eg, cost per additional progression-free month, cost per quality-adjusted lifeyear) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Clinic/laboratory visits will occur weekly for Weeks 1 through 8, every 4 weeks at Weeks 12, 16, 20, and 24, and every 6 weeks between Weeks 24 and 48. Subjects continuing on study treatment past Week 48 will have clinic visits every 12 weeks. Subjects will be assessed for safety at each visit. Subjects will be assessed for CLL disease status by physical and laboratory examinations at each visit and by CT or MRI at Weeks 8, 16, 24, 36, 48 and every 12 weeks thereafter through Week 96. For follow-up visits after Week 96, CT or MRI is only required at the end-of-therapy visit. |
|
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Denmark |
| France |
| Ireland |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Sweden |
| 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 129th 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 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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