A Study of Idelalisib (<span class="go-doc-concept go-doc-intervention">GS1101</span>, CAL101) + <span class="go-doc-concept go-doc-intervention">Ofatumumab</span> in Previously Untreated CLL/SLL
Brief Title: A Study of Idelalisib (GS1101, CAL101) + Ofatumumab in Previously Untreated CLL/SLL
Official Title: A Phase II Study of Idelalisib (GS1101, CAL101) + Ofatumumab in Previously Untreated Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Leukemia (SLL)
Clinical Trial IDs
NCT ID: NCT02135133
ORG ID: 13-309
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
||Idelalisib & Ofatumumab
||Idelalisib & Ofatumumab
This research study is evaluating a combination of drugs called Ofatumumab and Idelalisib as
a possible treatment for Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Leukemia
The main purpose of this study is to examine the combination of the two drugs, Ofatumumab
and Idelalisib, in participants who have been diagnosed with CLL/SLL and have not previously
received treatment but do require treatment. The investigators hope to observe how
participants' disease will be impacted by this treatment and whether they will benefit more
from combining these drugs together rather than taking them separately. Both of these drugs
have been used in treatment for CLL / SLL and information from those research studies
suggests that these drugs may help patients with CLL/SLL.
Ofatumumab is an antibody engineered in the lab against CD20, a protein on the surface of
CLL cells, which is expressed in CLL. An antibody is a molecule your body creates to
identify foreign substances so that it can destroy them. Ofatumumab has been FDA approved
for treatment of CLL/SLL that has relapsed or progressed on other therapies. Idelalisib is a
drug that blocks one of the signals inside the cells that cause this type of cancer to grow
and survive. The investigators hope that combining Ofatumumab with Idelalisib will stop the
growth of disease.
In this research study, the investigators are evaluating the side effects of combining these
two drugs, gathering information on the CLL/SLL disease process and how the study affects
the patient's cells, as well as assessing the outcome of the disease. This combination of
drugs has been previously tested, and appeared to be well tolerated.
Before the research starts (screening): After signing the consent form, the participant will
be asked to undergo some screening tests or procedures to find out if they are eligible to
be in this research study. Many of these tests and procedures are likely to be part of
regular cancer care and may be done even if it turns out that the participant does not take
part in the research study. If the participant has had some of these tests or procedures
recently, they may or may not have to be repeated.
- A medical history, which includes questions about the participant's health, current
medications, and any allergies.
- Physical examination, which includes vital signs, height, weight, and disease
assessment by the size of the participant's spleen, liver, and lymph nodes.
- Performance status, which evaluates how the participant is able to carry on with their
- An assessment of the patient's tumor by CT (Computerized Tomography) scan, MRI or PET
(Positron Emission Tomography) scans,
- Bone marrow aspirate and biopsy: A study tube (plastic cylinder container that contains
biopsy material) will be drawn during this biopsy to further assess the participant's
- Blood tests, a maximum of 24 teaspoons will be collected.
- Urine test.
- A blood pregnancy test
- A Hepatitis B and C test, will require blood sample.
If these tests show that the participant is eligible to participate in the research study,
then the participant will be begin will begin the study treatment. If you do not meet the
eligibility criteria, the participant will not be able to participate in this research
Additional research procedures to be performed at the time of screening:
Blood tests, including baseline tests so that the investigators can measure any additional
effect of the study drug and disease status
After the screening procedures confirm that you are eligible to participate in the research
If you take part in this research study, the participant will be given a study drug-dosing
diary for each treatment cycle. Each treatment cycle lasts 28 days. The diary will also
include special instructions for taking the study drugs.
- Study Drugs: The participant will first be given Idelalisib daily for two cycles of 28
days each. Idelalisib will be given orally. Once the participant completes 2 cycles of
Idelalisib, then the participant will start to receive a combination of Ofatumumab and
Idelalisib. This regimen will continue weekly to complete 8 weeks (two more cycles).
This will be followed by monthly Ofatumumab and Idelalisib to complete 4 additional
cycles (eight total). The overall treatment period will therefore be 8 months,
comprised of two months of Idelalisib followed by 6 months of Ofatumumab with
Idelalisib. After completing the 8-month treatment, the participant will likely
continue Idelalisib. Restaging with CT scans will happen after Cycle 2, 4, and a final
restage will occur 2 months after the completion of Ofatumumab. There will be a tumor
response assessment done during a physical exam after Cycle 8.
- Clinical Exams: During all cycles the participant will have a physical exam and will
be asked questions about their general health and specific questions about any problems
that they might be having and any medications they may be taking.
- Scans (or Imaging tests): The investigator will assess the participant's tumor by CT
scan. Restaging with CT scans will happen after Cycle 2, 4, and a final restage will
occur 2 months after the completion of Ofatumumab.
- Bone marrow aspirate and biopsy: will be conducted to see if the bone marrow has tumor
cells. A study tube will be drawn during this biopsy to further assess the patient's
- Blood tests
Additional Blood Tests:
Blood Tests will be performed throughout the study so that the Investigator can measure any
additional effect of the study drug and disease status. These tests will be taken on the
days listed below before the participant receive study drug, on some days additional blood
will be drawn after they receive study drug.
Cycle 3 Day 1 Cycle 3 Day 8 Cycle 3 Day 15 Cycle 4 Day 21 (last weekly Ofatumumab dose)
Cycle 5 Day 1 (first monthly Ofatumumab dose) Cycle 8 Day 1 (last monthly Ofatumumab dose) 2
months after Ofatumumab therapy completed 6 months after Ofatumumab therapy completed
Once the participant has completed the study treatment, the participant will be monitored
until they start a new type of treatment or are removed from the study. During this time the
participant will meet with your research physician every 3 or 6 months.
The investigator would like to keep track of the participant's medical condition for the
rest of their life. The investigator would like to do this by calling the participant on
the telephone once a year to see how the participant is doing. Keeping in touch with the
participant and checking their condition every year helps the investigator look at the
long-term effects of the research study.
|Idelalisib & Ofatumumab
||Idelalisib will be given orally continuously at 150 mg BID. On day 57, ofatumumab will begin with the 300 mg dose, given after idelalisib is taken. Ofatumumab will then be administered at 1000 mg weekly to complete 8 weeks (days 64, 71, 78, 85, 92, 99, 106) throughout Cycles 3 and 4. This will be followed by monthly ofatumumab on weeks 20, 24, 28, 32 to complete 4 additional cycles (5-8). The overall induction treatment period will then be 8 months, comprised of two months of single agent idelalisib followed by 6 months of ofatumumab with idelalisib. After the completion of the induction treatment, idelalisib will continue indefinitely in arbitrarily defined 28 day cycles in all participants who have not had excessive toxicity and do not have progressive disease.
- Participants must meet the following criteria on screening examination to be eligible
to participate in the study:
- Subjects must have CLL / SLL, as documented by a history at some point of an absolute
peripheral blood B cell count > 5000, with a monoclonal B cell population
co-expressing CD19, CD5, and CD23, or if CD23 negative, then documentation of the
absence of t(11;14) or cyclin D1 overexpression. Alternatively patients with
lymphadenopathy in the absence of circulating disease will also be eligible for this
study if lymph node biopsy establishes the diagnosis of CLL with the above
- Participants must have measurable disease (lymphocytosis > 5,000, or palpable or CT
measurable lymphadenopathy > 1.5 cm, or bone marrow involvement >30%).
- Subjects must not have received any prior systemic therapy for CLL and currently have
an indication for treatment as defined by the IWCLL 2008 Guidelines:
- Massive or progressive splenomegaly; OR
- Massive lymph nodes, nodal clusters, or progressive lymphadenopathy; OR
- Grade 2 or 3 fatigue; OR
- Fever 100.5F or night sweats for greater than 2 weeks without documented
- Presence of weight loss 10% over the preceding 6 months; OR
- Progressive lymphocytosis with an increase of 50% over a 2-month period or an
anticipated doubling time of less than 6 months; OR
- Evidence of progressive marrow failure as manifested by the development of or
worsening of anemia and or thrombocytopenia.
- ECOG performance status <2 (see Appendix A).
- Age 18 years. Because no dosing or adverse event data are currently available on
the use of idelalisib or ofatumumab in participants <18 years of age, children are
excluded from this study.
- Participants must have normal organ and marrow function as defined below:
- creatinine <2.0 times upper normal limit, total bilirubin <1.5 times upper normal
limit (unless due to disease involvement of liver, hemolysis or a known history of
- ALT <2.5 times upper normal limit (unless due to disease involvement of liver)
alkaline phosphatase <2.5 times upper normal limit (unless due to disease involvement
of the liver or bone marrow)
- Ability to understand and the willingness to sign a written informed consent
- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.
- Participants who have had any prior systemic therapy for CLL, or chemotherapy or
radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) for some other
indication prior to entering the study or those who have not recovered from adverse
events due to agents administered more than 4 weeks earlier.
- History of severe allergic reactions attributed to compounds of similar chemical or
biologic composition to ofatumumab or idelalisib.
- Subjects who have current active hepatic or biliary disease (with exception of
participants with Gilbert's syndrome, asymptomatic gallstones, liver metastases or
stable chronic liver disease per investigator assessment)
- Treatment with any known non-marketed drug substance or experimental therapy within 5
terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently
participating in any other interventional clinical study
- Other past or current malignancy that could interfere with the interpretation of
outcome. Subjects who have been free of active malignancy for at least 2 years, or
have a history of completely resected non-melanoma skin cancer or successfully
treated in situ carcinoma, or whose malignancy will not interfere with the
interpretation of study results, are eligible.
- Chronic or current infectious disease requiring systemic antibiotics, antifungal, or
antiviral treatment such as, but not limited to, chronic renal infection, chronic
chest infection with bronchiectasis, tuberculosis and active Hepatitis C.
- History of significant cerebrovascular disease in the past 6 months or ongoing event
with active symptoms or sequelae
- Known HIV positive. HIV-positive individuals on combination antiretroviral therapy
are ineligible because of the potential for pharmacokinetic interactions with
idelalisib. In addition, these individuals are at increased risk of lethal infections
when treated with marrow-suppressive therapy. Appropriate studies will be undertaken
in participants receiving combination antiretroviral therapy when indicated.
- Clinically significant cardiac disease including unstable angina, acute myocardial
infarction within six months prior to randomization, congestive heart failure (NYHA
III-IV), and arrhythmia unless controlled by therapy, with the exception of extra
systoles or minor conduction abnormalities.
- Significant concurrent, uncontrolled medical condition including, but not limited to,
renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or
psychiatric disease which in the opinion of the investigator may represent a risk for
- Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB
DNA test will be performed and if positive the subject will be excluded.
- If HBV DNA is negative, subject may be included but must undergo HBV DNA PCR testing
at least every 2 months from the start of treatment until 12 months post treatment.
Prophylactic antiviral therapy may be initiated at the discretion of the
- Positive serology for hepatitis C (HC) defined as a positive test for HepC Ab, in
which case reflexively perform an HC RIBA immunoblot assay or hepatitis C viral load
to confirm the result. If the confirmatory test is negative the subject will be
- Pregnant or lactating women.
- Women of childbearing potential, including women whose last menstrual period was less
than one year prior to screening, unable or unwilling to use adequate contraception
from study start to 30 days after the last dose of protocol therapy. Adequate
contraception is defined as hormonal birth control, intrauterine device, double
barrier method or total abstinence.
- Male subjects unable or unwilling to use adequate contraception methods from study
start to 30 days after the last dose of protocol therapy.
- Participants using concomitant corticosteroids are allowed as long as the subject is
on the equivalent of 20mg/day or less of prednisone and has been on a stable dose for
at least two weeks prior to initiating therapy.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
Primary Outcome Measures
Overall Response Rate of ofatumumab and idelalisib in previously untreated CLL/SLL participants in need of therapy
Secondary Outcome Measures
CR rate and PFS of ofatumumab and idelalisib.
ORR, CR rate and rate of nodal PR with lymphocytosis for idelalisib given alone for two months of therapy to previously untreated participants
Frequency of lymphocytosis with single agent idelalisib in previously untreated participants
Frequency of serious adverse events while on treatment with idelalisib and ofatumumab
Correlation of clinical response with known CLL molecular prognostic factors including FISH, IGHV, ZAP-70.
Contribution of CT scans to response assessment
Correlation of serum ofatumumab and/or idelalisib levels in vivo with response.
Cell surface marker phenotype of circulating CLL cells.
Impact of in vivo treatment with idelalisib on CLL cell sensitivity to therapy with antibodies or other kinase inhibitors.
Pharmacodynamic markers of PI3 kinase inhibition including AKT phosphorylation, production of T cell chemokines and response to CXCR 4/5.
Correlation of genetic alterations in PIK3CA or PIK3CD or other genes with response or resistance ot idelalisib
Influence of idelalisib treatment on intrinsic innate immune suppression and on regulatory T cells.
Prediction of response and resistance to idelalisib through biochemical and genetic analysis of the PI3K pathway.
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma