| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 examine the efficacy of IPI-145 monotherapy versus ofatumumab monotherapy in subjects with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) |
|
| E.2.2 | Secondary objectives of the trial |
•To determine the safety of IPI-145 in subjects with CLL and SLL
•To evaluate the pharmacokinetics (PK) of IPI-145 and, if applicable, its metabolite(s)
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| There is an optional sub study for Pharmacogenomics. There is not a separate protocol, it is included in the main protocol. |
|
| E.3 | Principal inclusion criteria |
Subjects are eligible for inclusion in the study if they meet the following
criteria:
1. ≥ 18 years of age
2. Diagnosis of active CLL or SLL that meets at least one of the IWCLL
2008 criteria for requiring treatment (Binet Stage ≥ B and/or Rai Stage
≥ I)
3. Disease that has progressed during or relapsed after at least one
previous CLL/SLL therapy
4. Not appropriate for treatment with a purine-based analogue regimen
(per National Comprehensive Cancer Network [NCCN] or European
Society for Medical Oncology [ESMO] guidelines), including relapse ≤ 36
months from a purine-based chemoimmunotherapy regimen or relapse ≤
24 months from a purine-based monotherapy regimen
5. A cytogenetics or fluorescence in situ hybridization (FISH) analysis
of the leukemic cells within 24 months of randomization is required to
document the presence or absence of del(17p). Note: if a sample from within 24 months is not available, it should be evaluated as part of the
screening laboratory evaluation to inform stratification
6. Measurable disease with a lymph node or tumor mass > 1.5 cm in at
least one dimension as assessed by computed tomography (CT)
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 2 (corresponds to Karnofsky Performance Status [KPS] ≥ 60%)
8. Willingness by subject to be randomized to receive either
ofatumumab or duvelisib at the dose and schedule defined in the
protocol
9. Must meet the following laboratory parameters:
a. Serum aspartate transaminase (AST/SGOT) or alanine transaminase
(ALT/SGPT) ≤ 3 x upper limit of normal (ULN)
b. Total bilirubin ≤ 1.5 x ULN
c. Serum creatinine ≤ 2.0 x ULN
d. Hemoglobin ≥ 8.0 g/dL with or without transfusion support
e. Platelet count ≥ 10,000 μL with or without transfusion support
10. For women of childbearing potential (WCBP): negative serum β-
human chorionic gonadotropin (βhCG) pregnancy test within 1 week
before randomization (WCBP defined as a sexually mature woman who
has not undergone surgical sterilization or who has not been naturally
post-menopausal for at least 24 consecutive months [women ≤ 55
years] or 12 consecutive months [women > 55 years])
11. Willingness of male and female subjects who are not surgically
sterile or postmenopausal to use medically acceptable methods of birth
control from the first dose of study drug to 30 days after the last dose of
duvelisib and for 12 months after last dose of ofatumumab. Sexually
active men, and women using oral contraceptive pills, should also use
barrier contraception
12. Ability to voluntarily sign consent for and adhere to the entire study
visit schedule and all protocol requirements
13. Signed and dated institutional review board (IRB)/independent
ethics committee (IEC)-approved informed consent form |
|
| E.4 | Principal exclusion criteria |
Subjects are to be excluded from the study if they meet any of the
following criteria:
1. History of Richter's transformation or prolymphocytic leukemia
2. Autoimmune hemolytic anemia (AIHA) or idiopathic
thrombocytopenic purpura (ITP) that is uncontrolled or requiring > 20
mg once daily (QD) of prednisone (or equivalent) to maintain
hemoglobin > 8.0 g/dL or platelets > 10,000 μL without transfusion
support
3. Refractory to ofatumumab (defined as progression or relapse <12
months of receiving ofatumumab monotherapy or < 24 months of
receiving an ofatumumab-containing regimen)
4. Prior allogeneic transplant (prior autologous stem cell transplant >6
months prior to study entry is permitted)
5. Known central nervous system (CNS) lymphoma or leukemia;
subjects with symptoms of CNS disease must have a negative CT scan or
negative diagnostic lumbar puncture prior to randomization
6. Prior exposure to a phosphoinositide-3-kinase (PI3K) inhibitor (eg,
GS-1101, duvelisib) or a Bruton's tyrosine kinase (BTK) inhibitor
7. Use of any of the following medications or procedures within the
specified timeframe:
Use of live or live attenuated vaccines within 30 days prior to
randomization
Chemotherapy, radiation therapy, or ablative therapy within 3 weeks
of randomization Tyrosine kinase inhibitor within 7 days of randomization
Other investigational therapy (not included above) within 3 weeks of
randomization
8. Ongoing treatment with chronic immunosuppressants (eg,
cyclosporine) or systemic steroids > 20 mg prednisone (or equivalent)
QD
9. History of tuberculosis treatment within the preceding two years
10. Ongoing systemic bacterial, fungal, or viral infections at the time of
initiation of study treatment (defined as requiring IV antimicrobial,
antifungal or antiviral agents)
Subjects on antimicrobial, antifungal or antiviral prophylaxis are not
specifically excluded if all other inclusion/exclusion criteria are met and
there is no evidence of active infection at randomization
11. Human immunodeficiency virus (HIV) infection
12. Prior, current, or chronic hepatitis B or hepatitis C infection
13. History of alcohol abuse or chronic liver disease (other than
metastatic disease to the liver)
14. Unable to receive prophylactic treatment for pneumocystis or
herpes simplex virus (HSV)
15. Baseline QT interval corrected with Fridericia's method (QTcF) >
480 ms (average of triplicate readings) Note: This criterion does not
apply to subjects with a right or left bundle branch block (BBB)
16. Unstable or severe uncontrolled medical condition (eg, unstable
cardiac function, unstable pulmonary condition), or any important
medical illness or abnormal laboratory finding that would, in the
investigator's judgment, increase the subject's risk while participating in
this study
17. Concurrent active malignancy other than nonmelanoma skin cancer
or carcinoma in situ of the cervix, bladder, or prostate not requiring
treatment. Subjects with previous malignancies are eligible provided
that they have been disease free for ≥2 years
18. History of stroke, unstable angina, myocardial infarction, or
ventricular arrhythmia requiring medication or mechanical control within
the last 6 months
19. Administration of medications or foods that are strong inhibitors or
inducers of CYP3A within 2 weeks of randomization
20. Prior surgery or gastrointestinal dysfunction that may affect drug
absorption (eg, gastric bypass surgery, gastrectomy)
21. Major surgery or invasive intervention within 4 weeks prior to
randomization
22. Pregnant or breastfeeding women
23. Hypersensitivity to ofatumumab or its excipients |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is progression-free survival (PFS), defined as time
from randomization to first documentation of progressive disease (PD)
as determined by independent review or death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, cycles 3, 5, 7, 11, 15 and 19, and early termination from
study treatment |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
• Overall Response Rate (ORR), with overall response (based on
independent review) defined as best response of complete
response/remission (CR), CR with incomplete marrow recovery (CRi),
partial response/remission (PR), or PR with lymphocytosis (PRwL),
according to the IWCLL or revised IWG Response Criteria, with
modification for treatment-related lymphocytosis
• Lymph node response rate, with lymph node response defined as ≥
50% decrease in the sum of the products (SPD) of target lymph nodes
• Overall Survival (OS), defined as time from randomization to death
• Hematologic improvement rate, with hematologic improvement
defined as any of following, for at least 60 days without transfusion or
exogenous growth factors:
o Neutrophil count > 1,500/μL or an increase ≥ 50% from Baseline; or
o Hemoglobin > 11 g/dL or an increase ≥ 50% from Baseline; or
o Platelet count >100,000/μL or an increase ≥ 50% from Baseline
• Duration of Response (DOR), defined as time from the first
documentation of response to first documentation of PD or death due to
any cause
• Treatment-emergent adverse events (TEAEs) and changes in safety
laboratory values
• PK parameters derived from plasma duvelisib concentrations and, if
applicable, its metabolite(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, cycles 3, 5, 7, 11, 15 and 19, and early termination from
study treatment |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 62 |
| 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 |
| Austria |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| New Zealand |
| Spain |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 6 |
| 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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