| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory leukemias |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000880 |
| E.1.2 | Term | Acute myeloid leukaemia |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I component:
To determine the safety, tolerability and recommended Phase II dose and regimen of GSK1120212 given orally.
Phase II component:
To evaluate clinical efficacy after treatment with GSK1120212. |
|
| E.2.2 | Secondary objectives of the trial |
Phase I component:
1. To characterize the PK of GSK1120212 after single- and repeat-dose administration.
2. To evaluate the PD response after treatment with GSK1120212.
Phase II component:
1. To characterize the PK of GSK1120212 after single- and repeat-dose administration. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
3. For Cohort 2, subject must be 18 years old or greater and be known NRAS or KRAS wildtype or unknown mutation status.
4. For Cohort 3, subjects must also meet the below criteria:
• Subject has a KRAS or NRAS mutation.
• At least 60 years of age.
• Diagnosed with relapsed or refractory AML, MDS with greater than 5% blasts in the marrow, or CMML with greater than 5% blasts in the marrow
• Has received at least one prior anti-leukemia therapy from this list:
i. Low-to intermediate dose Ara-c, at least 5 days of dosing between 40 mg/ m2 and 1000 mg/m2
ii. At least 3 cycles of hypomethylating agent which ended in progressive disease or at least 6 cycles with no response OR, in a patient with AML and prior MDS, at least one cycle of hypomethylating agent which ended in progression
iii. An ara-c combination and anthracycline (7 and 3)
|
|
| E.4 | Principal exclusion criteria |
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 (myelotarg) 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 (Section 8.2.1) 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 (LMWH) 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 (RVO) or central serous retinopathy (CSR), 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 (CNS) 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-epileptic drugs (EIAEDs).
18. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, or cardiac disease).
19. Unresolved toxicity greater than common terminology criteria for adverse events (CTCAE) Grade 1 from previous anti-cancer therapy except alopecia (if applicable) unless agreed to by a GSK Medical Monitor and the investigator.
20. QTcB 480 msec.
21. History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty or stenting within the past 6 months.
22. History or evidence of current > Class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system.
23. Uncontrolled arrhythmias.
24. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, dimethyl sulfoxide (DMSO).
25. Pregnant or lactating female.
26. History of interstitial lung disease or pneumonitis.
27. Unwillingness or inability to follow the procedures outlined in the protocol.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I component:
1. AEs and changes in laboratory values and vital signs.
Phase II component:
1. Objective response rate (% of patients achieving CR, PR, CRp or morphologic leukaemia-free state) per response criteria as described (Appendix 1). |
|
| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| refer to protocol - The end of the study is defined as the last subject’s last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
