| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cancer (malignant solid tumors) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
PART A
To determine the maximum tolerated dose (MTD) and evaluate the safety and tolerability of multiple ascending doses of VX 970 administered once weekly (Part A1) or twice weekly (Part A2) as a single agent in subjects with advanced solid tumors
PART B
To determine the maximum tolerated dose and evaluate the safety and tolerability of VX 970 when administered in combination with carboplatin (Part B1) and with carboplatin and paclitaxel (Part B2) in subjects with advanced solid tumors
PART C
To evaluate the safety and tolerability of VX 970 administered as a single agent followed by administration of VX 970 in combination with carboplatin in subjects with solid tumors and lymphoma with tumor genotypes and/or phenotypes of interest based on defects in the DDR, the mechanism of action of VX 970, and on data from ongoing clinical studies |
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| E.2.2 | Secondary objectives of the trial |
PART A
- Evaluate PK of VX-970 when administered as a single agent
- Assess potential antitumour responses after administration of VX-970
PART B
- Evaluate PK of VX-970 when administered in combination with carboplatin (part B1) and with carboplatin and paclitaxel (Part B2)
- Assess potential antitumour responses after administration of VX-970 in combination with carboplatin (part B1) and with carboplatin and paclitaxel (Part B2)
- Assess response duration after administration of VX-970 in combination with carboplatin (part B1) and with carboplatin and paclitaxel (Part B2)
PART C
- Assess antitumour responses after administration of VX-970 as a single agent and in combination with carboplatin
- Evaluate PK of VX-970 when administered as a single agent and in combination with carboplatin
- Assess response duration after administration of VX-970 as a single agent and in combination with carboplatin |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who meet all of the following inclusion criteria will be eligible for this study:
1 Male and female subjects ≥18 years of age
2 Disease status
Parts A1, A2, B1 and B2: Subjects with histologically or cytologically confirmed malignant advanced solid tumors refractory to standard therapy or for which no suitable effective standard therapy exists
a Parts A1 and A2: Subjects will preferentially have mutations known to be involved in the DDR, e.g., ATM or TP53 genes identified by sequencing of tumor tissue derived DNA, using a platform such as the Illumina MiSeq.
b Part B1: In the MTD expansion cohort, at least 6 subjects must have disease sites amenable for paired biopsies
Part C: Subjects must have histologically or cytologically confirmed malignant advanced solid tumors or lymphoma and have tumor genotypes and/or phenotypes of interest based on defects in the DDR, the mechanism of action of VX 970, or on data from ongoing clinical studies
3 Measurable disease according to RECIST criteria (Version 1.1)
4 WHO performance status of 0 or 1
5 Life expectancy of ≥12 weeks
6 Hematological and biochemical indices within the ranges shown below at Screening. These values must be confirmed at the first day of dosing, before study drug administration
a Hemoglobin: ≥9.0 g/dL
b Absolute neutrophil count: ≥2.0 × 109/L
c Platelet count: ≥150 × 109/L
d Serum bilirubin: ≤1.5 × upper limit of normal (ULN), unless the subject has known or suspected Gilbert’s syndrome
e Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): ≤2.5 × (ULN) or ≤5 × ULN in presence of liver metastases
f Estimated glomerular filtration rate: ≥50 mL/min
g Prothrombin time: <1.5 × ULN
h In addition, there should not be other clinically significant metabolic or hematologic abnormalities that are uncorrectable or that require ongoing, recurrent pharmacologic management
7 Sign and date an informed consent document
8 Willing and able to comply with scheduled visits, treatment plan, lifestyle, laboratory tests, contraceptive guidelines, and other study procedures
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| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not eligible for this study:
1 Radiotherapy unless brief course for palliative therapy, endocrine therapy (except for ongoing luteinizing hormone releasing hormone agonist therapy for subjects with prostate cancer who have progressed), immunotherapy, or chemotherapy during the 4 weeks (6 weeks for nitrosoureas and Mitomycin C, and 4 weeks for IMP) or 4 drug half lives before first dose of study drug, whichever is greater
2 Ongoing toxic manifestations of previous treatments including known history of Grade 4 thrombocytopenia with any prior chemotherapy regimen, unless approved by the Vertex Medical Monitor. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the investigator should not exclude the subject
3 Spinal cord compression or brain metastases unless asymptomatic, treated, stable, and not requiring steroids for at least 4 weeks before first dose of study drug. Any history of leptomeningeal metastases.
4 Female subjects who are already pregnant or lactating, or plan to become pregnant within 6 months of the last dose of study drug are excluded. Female subjects of childbearing potential must adhere to contraception guidelines as outlined in Section 11.6.5.1. Female subjects will be considered to be of nonchildbearing potential if they have undergone surgical hysterectomy or bilateral oophorectomy or have been amenorrheic for over 2 years with a screening serum follicle-stimulating hormone level within the laboratory’s reference range for postmenopausal females
5 Male subjects with partners of childbearing potential must agree to adhere to contraception guidelines in Section 11.6.5.1. Men with pregnant or lactating partners or partners who plan to become pregnant during the study or within 6 months of the last dose of study drug are excluded
6 Major surgery ≤4 weeks before first dose of study drug, or incomplete recovery from a prior major surgical procedure
7 Cardiac conditions as follows:
a Clinically significant cardiovascular event within 6 months before study entry:
i congestive heart failure requiring therapy
ii unstable angina pectoris
iii myocardial infarction
iv Class II/III/IV cardiac disease
v presence of severe valvular heart disease;
vi presence of a ventricular arrhythmia requiring treatment
b History of arrhythmia that is symptomatic or requires treatment (CTCAE 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted
c Uncontrolled hypertension (blood pressure ≥160/100 despite optimal therapy)
d Second or third degree heart block with or without symptoms
e QTc >470 msec not due to electrolyte abnormality and that does not resolve with correction of electrolytes
f History of congenital long QT syndrome
g History of torsades de pointes (or concurrent medication with a known risk of inducing torsades de pointes)
h Clinically-significant abnormality, including ejection fraction below normal institutional limits, present on transthoracic echocardiogram performed at Screening, for parts A1, A2, B1 and B2.
8 Prior bone marrow transplant or extensive radiotherapy to greater than 15% of bone marrow
9 Participation or plan of participation in another interventional clinical study while taking part in this study. Participation in an observational study would be acceptable
10 Any other condition which in the investigator’s opinion would not make the subject a good candidate for the clinical study, including:
a History of HIV 1, HIV 2, hepatitis C virus (HCV), or unresolved hepatitis B infection
b High medical risk because of non-malignant systemic disease including active uncontrolled infection
c History of serious allergy or autoimmune disease
d Subjects who have been diagnosed with Li-Fraumeni Syndrome or ataxia telangiectasia
11 Part C only: Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Subjects with prior malignancies that have been in remission for less than 3 years are excluded.
12 Current therapy:
a Subjects receiving treatment with medications that are known to be strong inhibitors or inducers of cytochrome P450 3A (CYP3A4) that cannot be discontinued at least 1 week before first dose of study drug and for the duration of the study
b For parts B1, B2 and C: subjects receiving treatment with ototoxic or nephrotoxic medications that cannot be discontinued at least 7 days before first dose of study drug and through the Safety Follow up Visit. Inadvertent or short term use on study will not cause a subject to be ineligible. If a short course of therapy with nephrotoxic or ototoxic medication is anticipated and required, carboplatin should be discontinued until 7 days after this course is completed.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Parts A:
- Safety parameters, including AEs, clinical laboratory values (serum chemistry and hematology), vital signs, and ECG assessments
-MTD of VX 970 administered once weekly (Part A1) or twice weekly (Part A2) as a single agent
Parts B:
- Safety parameters, including AEs, clinical laboratory values (serum chemistry and hematology), vital signs, and ECG assessments
-MTD of VX 970 administered in combination with carboplatin (Part B1) and with carboplatin and paclitaxel (Part B2)
Part C:
Safety parameters, including AEs, clinical laboratory values (serum chemistry and hematology), vital signs, and ECG |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluated continuously during dosing until 14 days after dosing. |
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| E.5.2 | Secondary end point(s) |
PART A:
- PK parameter estimates of VX 970, administered once weekly (Part A1) or twice weekly (Part A2) as a single agent, derived from plasma concentration time data
-Objective tumor response (OR) as evaluated by Response Criteria Evaluation (Response Evaluation Criteria in Solid Tumors [RECIST]) 1.1 and tumor markers
PART B
-PK parameter estimates of VX 970, administered in combination with carboplatin (Part B1) and with carboplatin and paclitaxel (Part B2), derived from plasma concentration time data
-OR as evaluated by Response Criteria Evaluation (RECIST) 1.1 and tumor markers
-Response duration as evaluated by Response Criteria Evaluation RECIST 1.1 and tumor markers
PART C
-OR as evaluated by Response Criteria Evaluation RECIST 1.1 and tumor markers
-PK parameter estimates of VX 970, administered as a single agent and in combination with carboplatin, derived from plasma concentration time data
-Response duration as evaluated by Response Criteria Evaluation RECIST 1.1 and tumor markers
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See section 11 of the protocol |
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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 | 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 | No |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| 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 | Yes |
| E.8.1.2 | Open | Yes |
| 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.8.5 | 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
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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
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