| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Triple-Negative Breast Cancer
Non-squamous Small Cell Lung Cancer
Squamous Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Selumetinib is a drug that acts by blocking a protein called MEK, which has been linked to the development and growth of multiple cancers. AZD2014 is a drug that blocks a protein called mTOR that is involved in the growth and spread of cancer. Blocking the action of either MEK or mTOR alone may slow down or stop the cancer growing. Combining both drugs may make the cancer more sensitive than if Selumetinib or AZD2014 are used alone and as such make this treatment more effective.
The principal research question for this study is to establish the feasible dose levels and regimens of AZD2014 and selumetinib when given in combination. Also, we will assess the clinical activity as measured by disease control rate, of AZD2014 and selumetininb in combination. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are as follows:
1) Assess the clinical activity as measured by patient response rate and change in tumour size of AZD2014 in combination with selumetinib
2) Establish the safety and tolerability of AZD2014 in combination with selumetinib
3) Determine the impact on the pharmacokinetics of AZD2014 and selumetinib when administered together
4) Assess progression-free survival, duration of response and overall survival of patients treatment with AZD2014 and selumetinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Written informed consent prior to admission to this study
2) Age ≥18 years
3) ECOG performance status 0 or 1
4) Life expectancy ≥ 12 weeks
5) Patients must have been at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥10mm in the longest diameter (except lymph nodes which must have short axis ≥15mm) with computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeatede measurements
6) Radiological or clinical evidence of disease progression
7) Formalin fixed, paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing
8) Adequate haematologic and end organ function, defined by laboratory results obtained within 14 days prior to the first study treatment
9) Female patients of child-bearing potential are eligible, provided they have a negative serum or urine pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception beginning 2 weeks before the first dose of investigational product and for 30 days after the final dose of investigational product. Male patients must agree to use appropriate contraception during the trial and for 3 months afterwards
Criteria unique to the Dose Escalation Part (Phase 1b part):
1) Histologically or cytologically advanced solid tumour; the study will be limited to
a) tumour types with frequent activation of MAPK and/or PI3K pathways (pancreatic, thyroid, endometrial, renal, breast or ovarian carcinoma, colorectal cancer, NSCLC or melanoma
b) tumours with known alteration in ≥1 gene involved in PI3K/AKT/mTOR or Ras/MEK pathway signalling, such as KRAS, NRAS, BRAF, PIK3CA, PTEN, AKT, LKB1, EGFR, FGFR, HER2, MET, RET, KIT
2) Metastatic or locally advanced disease, which is refractory to conventional treatment or for which no conventional therapy exists; locally recurrent disease must not be amenable to resection with curative intent
Criteria unique to the lung cancer dose expansion cohorts (phase IIa part):
1) Histologically confirmed non-small cell lung cancer
2) Stage III disease that is unsuitable to radio-chemotherapy or Stage IV disease or recurrent NSCLC; recurrent disease must not be amenable to resection or radical radiotherapy with curative intent
3) Prior chemotherapy and/or, if indicated/accessible, EGFR-directed or ALK-directed therapy for advanced disease
Criteria unique to the triple-negative breast cancer dose expansion cohort (phase IIa):
1) Histologically confirmed triple negative breast cancer
2) Metastatic or locally recurrent disease; locally recurrent disease must not be amenable to resection with curative intent
3) Prior chemotherapy for advanced disease |
|
| E.4 | Principal exclusion criteria |
1) Symptomatic CNS involvement or CNS involvement requiring steroid therapy; patients with treated brain metastases that are asymptomatic and have been clinically stable for 1 month will be eligible for protocol participation
2) Prior chemotherapy, biological therapy, radiation therapy, immunotherapy, other anticancer agents and any investigational agents within 14 days of starting study treatment
3) Any unresolved toxicity > CTCAE Grade 1 from previous anti-cancer therapy
4) Current refractory nausea and vomiting, chronic gastrointestinal disease or inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of the study medication
5) Significant cardiovascular disease
6) QTc prolongation defined as a QTc interval >470msecs
7) Concomitant medications known to prolong QT interval
8) Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroids for ≥28 days at the time of study entry
9)Evidence of interstitial fibrotic lung disease (bilateral, diffuse, parenchymal lung disease)
10) Clinically significant abnormalities of glucose metabolism
11) Opthalmological conditions as follows:
a) Intra-ocular pressure >21mmHg, or uncontrolled glaucoma
b) Current or past history of central serous retinopathy or retinal vein occlusion
12) Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 if taken within the stated washout period before the first dose of study treatment
13) Exposure to potent or moderate inhibitors or inducers of CYP2C8 within the stated washout periods before the first dose of study treatment
14) Exposure to sensitive or narrow therapeutic range substrates of the drug metabolising enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp and BCRP within the appropriate wsh-out period before the first dose of study treatment
15) Active second malignancy (except non-melanomatous skin cancer); active secondary malignancy is defined as a current need for cancer therapy or a high possibility of recurrence during the study
16) Any evidence or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
17) Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that in the investigators opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent
18) Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
19) Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study entry
Criteria specific to dose expansion cohorts:
1) Prior treatment with PI3K inhibitors, AKT inhibitors, mTOR inhibitors or MEK, Ras or Raf inhibitors
2) Prior radiotherapy to the indicator lesion(s); newly arising lesions in previously irradiated areas are accepted |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib:
Dose Limiting toxicities.
Phase IIa:
Disease control rate defined as complete (CR) or partial response (PR) or stable disease (SD) mantained ≥12 weeks (RECIST v1.1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase Ib: DLTs will be assessed at the end of each escalation cohort
Phase IIa: Will be assessed at baseline and every 6 weeks from Day 1 of cycle 1. |
|
| E.5.2 | Secondary end point(s) |
Phase Ib:
- Single dose and/or multiple dose AZD2014 PK parameters including Tmax, Cmax, and AUC
- Single dose and/or multiple dose selumetinib PK parameters including Tmax, Cmax, and AUC.
Phase IIa:
- ORR, defined as the number of patients with measurable disease at baseline with CR or PR (as assessed by the site radiologist, using RECIST 1.1) divided by the number of patients at risk
-Average change (%) in tumour size at 12 weeks compared to baseline as assessed by RECIST v1.1; tumour size is defined as the sum of the diameters of the target lesions.
-Safety and tolerability as assessed by Adverse Events (AEs) (CTCAE, v4.03).
-Single dose and/or multiple dose of AZD2014 and selumetinib PK parameters (e.g. including Tmax, Cmax, and AUC)
- PFS defined as the time from the date of registration to the date of first documented tumour progression (RECIST v1.1) or death from any cause, whichever occurs first.
-Duration of response defined as the time from first documentation of CR or PR to disease progression (RECIST v1.1) or death from any cause, whichever occurs first.
-Overall survival defined as the time from date of registration to the date of death due to any cause. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase Ib: Blood sampling for PK will be carried out at pre-defined time-points during Cycle 1.
Phase IIa:
- ORR will be assessed at baseline and every 6 weeks from Day 1 of cycle 1.
- Average change in tumour size Will be assessed at baseline and at 12 weeks.
- AEs will be collected at every study visit
- Blood sampling for PK analysis will be carried out at pre-defined time-points during Cycle 1.
- PFS will be assessed at baseline and every 6 weeks from Day 1 of cycle 1.
- Duration of response will be assessed at baseline and every 6 weeks from Day 1 of cycle 1.
- OS will be assessed at every visit (on treatment) and every 3 months until all patients have died or have been followed up for at least 18 months after registration of the last patient on study, whichever is sooner. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 study' is defined as the date when all patients have died or have been followed up for at least 18 months after registration. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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