| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Subjects with advanced solid tumors, non-hodgkin lymphoma (NHL) and
multiple myeloma (MM).
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| E.1.1.1 | Medical condition in easily understood language |
| Certain types of cancer that do not respond to treatment or for whom no standard anticancer therapy exists |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. Determine the safety and tolerability of CC-115 when administered orally and to define the Non-Tolerated Dose and the Maximum Tolerated Dose.
2. Determine the PharmacoKinetics of CC-115. |
|
| E.2.2 | Secondary objectives of the trial |
1. Evaluate the extent of inhibition of phosphorylation of S6RP and/or 4E-BP1 for mTORC1 activity and AKT and/or other relevant biomarkers for mTORC2 activity, in blood, skin and/or tumor biopsies/aspirates, when available before and during treatment with CC-115.
2. Evaluate the inhibition of DNA-PK activity in skin samples irradiated by UV light and/or tumor biopsies/aspirates using pDNA-PK S2056 and/or other relevant biomarkers for DNA damage pathways before and during CC-115 treatment.
3. Provide information on the efficacy of CC-115. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Please refer to protocol section 7.2 for the complete inclusion criteria, which are summarized below.
•Men and women, 18 years or older, with histological or cytological confirmation of advanced unresectable solid tumors, non-hodgkin’s lymphoma (NHL), or multiple myeloma (MM), including those who have progressed on (or not been able to tolerate) standard anticancer therapy or for whom no other conventional therapy exists. Ewing’s sarcoma (ES) subjects may be 12 years or older.
•Consent to screening tumor biopsy (Part A optional; Part B mandatory except as specified for individual tumor types)
•ECOG PS 0 or 1
•Laboratory values: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; hemoglobin (Hgb) ≥ 9 g/dl; platelets ≥ 100 x 10^9/L; potassium within normal range or correctable with supplements; AST/SGOT and ALT/SGPT ≤ 2.5 x ULN or ≤ 5.0 x ULN if liver tumor is present; serum total bilirubin ≤ 1.5 x ULN; serum creatinine ≤ 1.5 x ULN or 24-hr clearance ≥ 50 mL/min; negative serum or urine pregnancy test within 72 hrs before starting study treatment in females of childbearing potential
Dose expansion part (Part B) of the protocol only:
•Consent to retrieve formalin-fixed, paraffin-embedded (FFPE) archival tumor tissue; an exemption waiver may be granted by the Sponsor in exceptional circumstances.
•Histologically-confirmed tumors of the following types. Please refer to the specific inclusion criteria applicable to each tumor type, described in protocol section 7.2, which are in addition to, or supersede, the above criteria where applicable:
-Glioblastoma multiforme (GBM) or gliosarcoma, excluding WHO Grade IV oligoastrocytoma
-Head & neck squamous cell cancer (HNSCC)
-Triple negative breast cancer (TNBC)
-Hormone receptor-positive breast cancer (HRPBC)
-Castration-resistant prostate cancer (CRPC)
-Ewings Family of Sarcomas
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|
| E.4 | Principal exclusion criteria |
Please refer to protocol section 7.2 for the complete exclusion criteria, which are summarized below.
•Symptomatic central nervous system metastases
•Known acute or chronic pancreatitis
•Any peripheral neuropathy ≥ NCI CTCAE grade 2
•Persistent diarrhea or malabsorption ≥ NCI CTCAE grade 2, despite medical management. Impaired ability to swallow
•Impaired cardiac function or clinically significant cardiac diseases, including any of the following: LVEF < 45% as determined by MUGA scan or ECHO; complete left bundle branch, or bifasicular, block; congenital long QT syndrome; persistent or history of clinically meaningful ventricular arrhythmias or atrial fibrillation; QTcF > 460 msec on screening ECG (mean of triplicate recordings); unstable angina pectoris or myocardial infarction ≤ 3 months prior to starting CC-115; other clinically significant heart disease such as congestive heart failure requiring treatment or uncontrolled hypertension (blood pressure ≥ 160/95 mmHg)
•Diabetes mellitus on active treatment, or subjects with either fasting blood glucose (FBG) ≥ 126 mg/dL (7.0 mmol/L), or HbA1c ≥ 6.5%
•Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
•Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half lives or 4 weeks, whichever is shorter, prior to starting study drug or who have not recovered from side effects of such therapy
•Major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy
•Pregnancy or breast feeding
•Adults of reproductive potential not employing two forms of birth control (defined in protocol section 7.2):
•Known HIV infection
•Known chronic hepatitis B or C virus (HBV/HCV) infection, unless this is comorbidity in subjects with HCC
•Concurrent active second malignancy for which the subject is receiving therapy, excluding non-melanomatous skin cancer or carcinoma in situ of the cervix
Dose expansion part (Part B) of the protocol only:
•Prior treatment with agents targeting both mTOR complexes (dual TORC1+TORC2 inhibitors) and/or PI3K/AKT pathways. However, prior treatment with isolated TORC1 inhibitors (e.g., rapalogs) is allowed in both parts of this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. The following safety endpoints: DLTs, NTD and MTD, evaluated using the NCI CTCAE criteria Version 4.
2. PK endpoints: Cmax, AUC, tmax, t1/2, CL/F, Vz/F and Accumulation Index of CC-115. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
DLT/NTD or MTD are not time-related endpoints.
During the Part A Cycle 1, DLTs and all available safety information will be reviewed on an ongoing basis by the Investigators and sponsor and summarized at the conclusion of each dose level. After completion of each dose cohort, the SRC will review the summarized data to determine the next step. Complete safety data for the Part A Cycle 1 will be summarized when all subjects have completed the first 28-day cycle.
Blood draws for PK assessments will be taken on day 1,2,15 and 22 during cycle 1, blood draws will be taken at C1D1, C1D15 for all patients and in addition at C1D2 and C1D22 only for Ewings Sarcoma patients under 18 and for adult patients in US |
|
| E.5.2 | Secondary end point(s) |
1.Biomarker inhibition, determined by change in the levels of phosphorylation of S6RP, and/or 4E-BP1, and/or AKT, and/or other relevant biomarkers in blood, skin and/or tumor biopsies/aspirates, when available.
2.Inhibition of UV-stimulated DNA-PK activity determined by levels of pDNA-PK and/or other relevant biomarkers in skin and/or tumor biopsies/aspirates, when available.
3.Antitumor efficacy, determined by response rates of each tumor type using tumorappropriate response criteria.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Blood for PD Biomarkers (Part B/US only);
2. UV-stimulated skin biopsy (US only);
3. Antitumor efficacy - Efficacy will be analyzed by each tumor type once all subjects have withdrawn from the study or completed 6 cycles.
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|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| 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) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 | No |
| 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 |
| France |
| Spain |
| United States |
|
| 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
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| LVLS: final safety assessment 28 +/- 2 days after last dose of the last subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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