| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| 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 | 10059515 | | E.1.2 | Term | Non-small cell lung cancer metastatic | |
| 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 1B component: To determine the safety, tolerability and recommended Phase II dose and regimen of GSK1120212 and everolimus dosed orally in combination.
Phase II component: To determine clinical activity of GSK1120212 and everolimus in subjects with KRAS-mutant NSCLC. | |
| E.2.2 | Secondary objectives of the trial | Phase 1B component:
1) To characterize the steady-state PK of GSK1120212 and everolimus
2) To evaluate the clinical activity of GSK1120212 and everolimus in subjects with solid tumors and pancreatic cancer.
3) To determine if changes in CA 19-9 levels correlate with radiographic response in subjects with pancreatic cancer
Phase II component:
1) To characterize the population pharmacokinetics (PK) parameters of GSK1120212 and everolimus when administered daily in subjects with KRASmutant NSCLC.
2) To characterize the durability of response in subjects achieving clinical benefit. | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | A subject will be eligible for inclusion in this study only if all of the following criteria
apply:
1. Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
2. Age 18 years old or older and able to swallow oral medication.
3. Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology
(ECOG) scale for Phase IB/Dose Escalation Cohort. Subjects with ECOG PS of 2
can be enrolled for Phase IB/Expansion Cohort and Phase II.
4. Tumor Type criteria:
• Phase IB/Dose Escalation Cohort
o Histologically or cytologically confirmed diagnosis of solid tumor malignancy:
That is relapsed/refractory
OR is potentially responsive to everolimus
OR for which there is no standard or curative therapy
OR for subjects who refuse standard therapy
• Phase IB/Expansion Cohort
o Pancreatic cancer: Histologically or cytologically confirmed diagnosis of metastatic pancreatic cancer. Subjects with locally advanced surgically unresectable disease are also eligible.
o Measurable disease by RECIST 1.1.
• Phase II
o KRAS- mutant NSCLC: Histologically or cytologically confirmed diagnosis of metastatic NSCLC
o Measurable disease by RECIST 1.1 [Eisenhauer, 2009].
5. Fasting glucose < 126mg/dL
6. Male subjects must agree to use one of the contraception methods listed in
Section 7.1.2. This criterion must be followed from the time of the first dose of
study medication until 4 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).
7. A female subject is eligible to participate if she is of:
• Non-childbearing potential defined as pre-menopausal females with a
documented tubal ligation or hysterectomy; or postmenopausal defined as 12
months of spontaneous amenorrhea [in questionable cases a blood sample with
simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and estradiol <
40 pg/mL (<140 pmol/L) is confirmatory]. Females on hormone replacement
therapy (HRT) and whose menopausal status is in doubt will be required to use
one of the contraception methods in Section 7.1.1 if they wish to continue their
HRT during the study. Otherwise, they must discontinue HRT to allow
confirmation of post-menopausal status prior to study enrollment. For most
forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy
and the blood draw; this interval depends on the type and dosage of HRT.
Following confirmation of their post-menopausal status, they can resume use of
HRT during the study without use of a contraceptive method.
• 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
4 weeks after the last dose of study medication.
Note: Oral contraceptives are not reliable due to potential drug-drug interaction
8. Calcium phosphate product ≤ 4.0 mmol2/L2 (50 mg2/dL2)
9. Adequate organ system function as defined in Table 10 of the protocol | |
| E.4 | Principal exclusion criteria | A subject will not be eligible for inclusion in this study if any of the following criteria
apply:
1. Malignancies related to HIV or solid organ transplant.
2. Primary malignant brain tumors.
3. Chemotherapy, radiotherapy, or immunotherapy within 28 days (or 42 days for prior nitrosoureas or mitomycin C) prior to the first dose of GSK1120212. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity are permitted with approval of a GSK Medical Monitor if dosing of that agent is terminated at least 14 days prior to the first dose of GSK1120212.
4. Use of an investigational anti-cancer drug within 28 days or 5 half-lives, whichever
is shorter preceding the first dose of GSK1120212 – 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.
5. Previous treatment with an mTOR inhibitor unless approved by GSK Medical
Monitor.
6. Previous treatment with GSK1120212.
7. History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or GSK
Medical Monitor, contraindicates their participation.
8. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study drug, DMSO, or excipients (see GSK1120212
Investigator Brochure [GlaxoSmithKline Document Number RM2007/00107/00].
(To date there are no known FDA approved drugs chemically related to
GSK1120212).
9. Use of a prohibited medication (as defined in Section 8.2).
10. 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 required therapeutic levels of LMWH must receive
approval from GSK Medical Monitor and monitored appropriately as clinically
indicated.
11. Gastrointestinal disease predicted to interfere with absorption of an oral drug,
systemic disease, major surgery, or social/psychological issues that in the opinion of
investigators would jeopardize compliance with protocol.
12. History of retinal vein occlusion (RVO) or central serous retinopathy (CSR).
13. Predisposing factors to RVO including uncontrolled hypertension, uncontrolled
diabetes, uncontrolled hyperlipidemia, and coagulopathy.
14. Visible retinal pathology as assessed by ophthalmologic exam that is considered a
risk factor for RVO or CSR.
15. Intraocular pressure > 21mm Hg as measured by tonography.
16. Glaucoma diagnosed within 1 month prior to study Day 1.
17. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression. Subjects previously treated for these conditions that are asymptomatic
and off corticosteroids for at least two weeks are permitted. Subjects are not
permitted to receive enzyme inducing anti-epileptic drugs (EIAEDs).
18. 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.
19. History of acute coronary syndromes (including unstable angina), coronary
angioplasty, or stenting within the past 24 weeks.
20. QTc interval ≥ 480 msecs.
21. Class II, III, or IV heart failure as defined by the New York Heart Association
(NYHA) functional classification system.
22. Pregnant or lactating female.
23. History or active hepatitis B or C.
24. History of HIV infection.
25. Subjects on chronic antifungal therapy.
26. Unwillingness or inability to follow the procedures outlined in the protocol. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Phase 1B:
AEs and changes in laboratory values and vital signs.
Phase II:
Response rate (CR + PR) of GSK1120212 and everolimus in KRAS-mutant NSCLC. | |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description | | Dose escalation (Ph1B) followed by confirmatory efficacy (PhII) in NSCLC | |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 | | 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
