A phase 1/II study to investigate how the drug GSK1120212 behaves, its safety and effectiveness in subjects with cancer of blood cells
- Conditions
- Relapsed or refractory leukemiasMedDRA version: 14.1Level: PTClassification code 10000880Term: Acute myeloid leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2009-017376-25-DE
- Lead Sponsor
- GlaxoSmithKline Research & Development Ltd
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 135
Phase I component
1.Written informed consent provided.
2.18 years old or older.
3.Subjects must have relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Subjects with poor-risk myelodysplasia (MDS) [i.e. refractory anemia with excess blasts (RAEB-1 or RAEB-2) by WHO classification] and chronic myelomonocytic leukemia (CMML) are also eligible. Relapsed/refractory leukemias include acute non-lymphocytic leukemia (AML) by WHO classification, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML) in blast crisis. Subjects with agnogenic myeloid metaplasia (AMM) are also eligible.
4.Subjects ? 60 years of age with AML who are not candidates for or have refused standard chemotherapy.
5.Subject who have previously received an autologous stem cell transplant are allowed if a minimum of three months has elapsed from the time of transplant (T0) and the subject has recovered from transplant-associated toxicities prior to the first dose of GSK1120212.
6.Subjects with a history of allogeneic stem cell transplant are eligible for study participation provided the following eligibility criteria are met:
•transplant was > 100 days prior to study enrollment.
•subject has not taken immunosuppressive medications for at least 1 month
•no signs or symptoms of graft versus host disease other than Grade 1 skin involvement
• no active infection
•subject meets the remainder of the eligibility criteria outlined in this protocol
7.Eastern Cooperative Oncology Group (ECOG) performance status of ?2.
8.Life expectancy of at least four weeks.
9.Able to swallow and retain oral medication.
10.Male subjects must agree to use one of the contraception methods listed in Section 7.1 This criterion must be followed from the time of the first dose of study medication until four weeks after the last dose of study medication. However, the Sponsor advises that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm).
11.A female subject is eligible to participate if she is of:
•Non-childbearing potential
•Child-bearing potential and agrees to use one of the contraception methods listed in Section 7.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until four weeks after the last dose of study medication.
Note: Oral contraceptives are not reliable due to potential drug-drug interaction.
12.CPP ? 4.0 mmol2/L2(50 mg2/dL2).
13.Adequate organ system function
Phase II component:
As for Phase I, except replace Criteria 2-4 with the following:
1.Histologically or cytologically confirmed diagnosis of relapsed or refractory acute myeloid leukemia (AML), poor-risk myelodysplasia (MDS) with greater than 5% blasts in marrow, or chronic myelomonocytic leukemia (CMML) with greater than 5% blasts in marrow. RAS status in the leukemic cells of bone marrow and peripheral blood must be determined prior to study entry for Cohort 1 and 3.
a.If a site has a RAS assay available which meets GSK approval, that site may use those results for study entry, but must have samples shipped prior to study entry for central testing.
2.For Cohort 1, subject must be 18 years old or greater and have a KRAS or NRAS mutation
1. Hematological malignancy associated with human immunodeficiency virus (HIV) infection or solid organ transplant.
2. Concurrent malignancy of solid tumors. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled.
Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above.
3. Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno- therapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization).
Note: For proliferative disease, hydroxyurea will be allowed during Week 1 and 2. See Section 8.1 for additional details.
4. Received corticosteroids or imatinib within 24 h of GSK1120212 administration.
5. Received gemtuzumab ozogamicin within two weeks of GSK1120212 adminstration.
6. Received an investigational anti-cancer drug within four weeks or 5 half-lives, whichever is shorter of GSK1120212 administration--as long as a minimum of 14 days has passed between the last dose of the prior investigational anti-cancer drug and the first dose of GSK1120212.
7. Received major surgery, radiotherapy, or immunotherapy within four weeks of GSK1120212 administration.
8. Received chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior nitrosourea or mitomycin C). Received chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last two weeks.
9. Received a MEK inhibitor.
10. Current use of a prohibited medication or requires any of these medications during treatment with GSK1120212.
11. Current use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within seven days prior to the first dose of GSK1120212. Low dose (prophylactic) low molecular weight heparin is permitted provided that subject’s PT and PTT meet entry criteria. Subjects requireing therapeutic levels of LMWH must receive approval from GSK Medical Monitor and be monitored appropriately as clinically indicated.
12. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
13. History of retinal vein occlusion or central serous retinopathy, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, hypercholesterolemia, or history of hyperviscosity or hypercoagulability syndromes).
14. Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR
15. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
16. Concurrent condition that in the investigator’s opinion would jeopardize compliance with the protocol.
17. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
• Subjects previously treated for these conditions that have had stable central nervous system disease (verified with consecutive imaging studies) for >3 months, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted.
• Subjects are not permitted to receive enzyme inducing anti-e
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Phase I component: <br>To determine the safety, tolerability and recommended Phase II dose and regimen of GSK1120212 given orally.<br><br>Phase II component: <br>To evaluate clinical efficacy after treatment with GSK1120212.;Secondary Objective: Phase I component: <br>1. To characterize the PK of GSK1120212 after single- and repeat-dose administration.<br>2. To evaluate the PD response after treatment with GSK1120212.<br><br>Phase II component: <br>1. To characterize the PK of GSK1120212 after single- and repeat-dose administration.<br>2. To evaluate the safety and tolerability of GSK1120212.;Primary end point(s): Phase I component:<br>1. AEs and changes in laboratory values and vital signs.<br><br>Phase II component:<br>1. Objective response rate (% of patients achieving CR, PR, CRp or morphologic leukaemia-free state) per response criteria as described (Appendix 1).<br>;Timepoint(s) of evaluation of this end point: Final analysis
- Secondary Outcome Measures
Name Time Method Secondary end point(s): PHASE 1: GSK1120212 PK parameters following single- (Day 1) and repeat-dose (Day 15) administration of GSK1120212, including AUC(0-inf), AUC(0-tau), Cmin, Ctau, Cmax, tmax, t1/2 (or t1/2, eff), time invariance and accumulation ratio.<br>Change in molecular markers (e.g., pERK) in bone marrow and blood samples.<br><br>PHASE 2. GSK1120212 PK parameters following single- (Day 1) and repeat-dose (Day 15) administration of GSK1120212.<br>Overall Survival (the time from the treatment start date until death from any cause);Timepoint(s) of evaluation of this end point: Upon final analysis