To determine appropriate dosing regimens for use in future clinical trials of GS 9820 in subjects with lymphoid malignancies.
ID
Source
Brief title
Condition
- Other condition
- Lymphomas Hodgkin's disease
Synonym
Health condition
Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia, indolent Hodgkin's Lymphoma
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the MTD within the tested GS-9820 dose range and regimens
Secondary outcome
To characterize the safety profile of GS-9820, determined 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 or ECGs. Enumeration and
description of any DLTs, serious adverse events, or adverse events leading to
discontinuation of study treatment.
To characterize the pharmacokinetic profile of GS-9820, based on blood sampling
performed at GS-9820 initial dosing (Day 1) and at steady state (Day 29).
To assess the pharmacodynamic effects of GS-9820 on base of flow cytometry and
ELISA.
Antitumor activity will be evaluated using standard response criteria for NHL
or for CLL
Patient Well-Being will be determined by the Changes from baseline in HRQL
domain and symptom scores based on the Functional Assessment of Cancer Therapy:
Lymphoma (FACT-Lym).
Background summary
B-cell lymphoid malignancies comprise the most common hematological
malignancies. These cancers arise from the accumulation of monoclonal B
lymphocytes in lymph nodes and often in organs such as blood, bone marrow,
lymph nodes, spleen, and liver. Among the variants of these cancers are
non-Hodgkin lymphomas (NHL) * including diffuse large B-cell lymphoma (DLBCL),
indolent non-Hodgkin lymphoma (iNHL), and mantle cell lymphoma (MCL) * chronic
lymphocytic leukemia (CLL), and Hodgkin lymphoma (HL). The goal of therapy for
these diseases is to induce tumor regression and delay tumor progression in
order to control disease-related complications and potentially extend life.
Patients who require treatment are commonly given chemotherapeutic and/or
immunotherapeutic agents. For any of these cancers, further sequential
therapies are given in an attempt to control disease manifestations. Despite
use of agents with differing mechanisms of action, progressive resistance to
treatment develops.
Patients with progressive disease have a poor prognosis; median survival for
these groups of patients is generally *2 years. Novel mechanisms of action are
needed to offer additional treatment options for patients with lymphoid
malignancies who are experiencing progressive
lymphadenopathy or symptoms due to disease progression. Knowledge of the
critical importance of PI3K* in B-cell biology and neoplasia has encouraged a
search for inhibitors of this enzyme that could provide new options in the
therapy of lymphoid malignancies, including CLL. Gilead Sciences, Inc has
developed novel drugs that can suppress tumor growth through targeting of PI3K
activity. High-throughput screening was the basis for the discovery of novel
agents that selectively inhibit PI3K isoform function. These efforts initially
led to identification of GS-1101 (also known as CAL-101), a 415-Dalton, orally
bio-available, investigational drug that represented a first-in-class selective
inhibitor of PI3K*.The nonclinical and early clinical findings with GS-1101
have created the foundation on which second-generation agents, such as GS-9820,
will be evaluated. The design and conduct of this study is supported by an
understanding of the natural history and current therapies for patients with
recurrent lymphoid cancers; knowledge of the safety and activity of the
predecessor compound, GS-1101 in patients with NHL, HL, and CLL; and the
nonclinical and clinical information regarding GS-9820.
Study objective
To determine appropriate dosing regimens for use in future clinical trials of
GS 9820 in subjects with lymphoid malignancies.
Study design
This clinical trial is a Phase 1b, open-label, dose-escalation and expansion
study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor
activity of GS 9820.
Intervention
GS-9820 will be administered on a BID schedule starting on Day 1.
Treatment will persist until the earliest of subject withdrawal from study,
disease progression, intolerable GS-9820-related toxicity, pregnancy,
substantial noncompliance with study procedures, or study discontinuation.
Dose escalation
Patients will be sequentially enrolled at progressively higher dose levels Dose
escalation will be performed with cohort sizes of 3 to 6 subjects using a
classic 3+3 design. First cohort will start at 50 mg/dose BID.
Any subject started at a lower dose level during the dose escalation phase
should be increased to 400 mg BID. A lower dose level of 200 mg is provided if
a subject requires a study drug dose modification.
Study burden and risks
The patient is subjected to investigations that would take place in their
regular care, but in the beginning more frequently to be able to monitor any
adverse reactions. This forces the patient to the hospital more often than
regular care. During the first 12 weeks the study requires patients to come to
the outpatient clinic for follow-up every two weeks. The next 12 weeks patients
will have to come monthly for a follow up visit. After that time patients will
have to come in for a follow-up every 6 weeks until week 48. The period that
follows patients have to come in for follow up every 12 weeks. Prior to each
visit to the outpatient clinic, a blood sample will be taken to check the blood
values. With regular care the patient would come monthly for follow up and will
get their blood levels checked. Additional blood draws will be as much as
possible combined with regular care.
The 1st 3 months, the patients are requested to complete a monthly
questionnaire. Then the questionnaire is completed at each clinic visit. Until
week 24 there is a CT scan done every 8 weeks. Then every 3 months. The 1st
year, this would involve 8 additional CT scans in CLL patients and 5 CT scans
in Hodgkin and Non Hodgkin's patients.
Studies in rats and dogs that received daily very high doses, showed the
following adverse reactions, reduction of lymphocyte, decrease in size of the
thymus, spleen and lymph nodes, bowel inflammation, increases in liver size and
inflammation of the liver, reduced sperm production.
GS 9820 is also given to a group of male volunteers with a fixed dose. None of
the subjects experienced serious side effects or adverse reactions were
observed in animal studies.
GS 9820 has been given to 39 patients. The following side effects have been
reported and might have been caused by GS-9820: diarrhea, fatigue, fluid
retention or swelling of the arms or legs, pain, fever, lung infection,
decreased appetite, back pain, cough, rash.
For these patients there are no curative options. There are no standard
treatments for these people available. The expectation is that the drug under
study is effective with acceptable toxicity.
East Blaine Street 199
Seattle, WA 98109
US
East Blaine Street 199
Seattle, WA 98109
US
Listed location countries
Age
Inclusion criteria
1) Male or female *18 years of age.
2) Diagnosis of B-cell iNHL, DLBCL, MCL, HL, or CLL as documented by medical records and with histology based on criteria established by the World Health Organization.
3) Prior treatment for lymphoid malignancy.
4) Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of *1 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) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, systemic corticosteroids, or investigational therapy) for the treatment of cancer *3 weeks before
the start of study therapy.
6) All acute toxic effects of any prior antitumor therapy resolved to Grade *1 before the start of study therapy (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, or 3 permitted).
7) Karnofsky performance score of *60.
8) Required baseline laboratory data (within 4 weeks prior to start of study therapy) as shown in the table below.
9) 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 GS-9820.
10) 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 start of study therapy (Visit 2) throughout the study treatment period and for 90 days following the last dose of GS-9820 and to refrain from sperm donation from the start of study treatment (Visit 2) throughout the study treatment period and for 90
days following the last dose of GS-9820.
11) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current disease status, medical condition, and the potential benefits and risks of alternative treatments for the subject*s cancer.
12) Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions.
13) 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.
Exclusion criteria
1) Known histological transformation to an aggressive form of NHL (ie, Richter transformation).
2) Known active central nervous system or leptomeningeal lymphoma.
3) 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).
4) History of a non-lymphoid 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 start of study therapy, 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.
5) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of start of study therapy (Visit 2).
6) Ongoing liver injury, chronic active HCV, HBV, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing 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) 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).
13) Ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of lymphoid malignancy. 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 lowdose 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.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-000360-19-NL |
| CCMO | NL40813.018.12 |