| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Solid tumors or lymphomas that have failed standard therapies or for which no standard treatment option(s) exist. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors that have spread to other parts of the body (advanced solid tumors) and cancer that begins in the immune cells (lymphomas) |
|
| 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 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10025324 |
| E.1.2 | Term | Lymphomas unspecified NEC |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 |
1. To provide previously enrolled and treated patients benefitting from the study drug with an
access to TSR-011
2. Phase 1 and 2a: To evaluate the safety and tolerability of orally administered TSR-011 (Not
applicable as of the current protocol amendment)
|
|
| E.2.2 | Secondary objectives of the trial |
1. To continue evaluation of the safety and tolerability of orally administered TSR-011
2. Phase 1: To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of TSR-011 (Not applicable as of the current protocol amendment)
3. Phase 1: To determine the pharmacokinetics of TSR-011 (Not applicable as of the current protocol amendment)
4. Phase 2: To determine the response rate and progression-free survival (PFS) to treatment with TSR-011 (Not applicable as of the current protocol amendment)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
After this protocol amendment, no new enrollment will take place. Only patients who were previously
enrolled and treated will be included in this study. Criteria previously used in this study were as follows:
1. Patients in Phase 1 must have metastatic or locally advanced solid tumors who have failed to respond to standard therapy, have progressed despite standard therapy, refuse standard therapy, or for whom standard therapy does not exist.
2. All patients must have confirmation of either ALK+ or TRK+ status prior to being enrolled. Pursuant to discussion between Investigators and the Sponsor tumors with additional markers may be allowed in Phase 2a, Cohort 3
• Note: This criterion does not apply to patients in the formulation
substudy, as formulation substudy entry criteria are broadened to
include all tumor types.
3. Patients in Phase 1 will not be required to have measurable disease. All patients in Phase 2a will be required to have measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST).
4. All patients enrolled in this study must have tumor tissue available. This typically may be from formalin-fixed paraffin-embedded blocks (preferred) or at least 20 unstained slides (where available). If archival tumor tissue is not available, a tumor biopsy is required.
•Note: For formulation substudy patients, this criterion does not need to
be met before enrollment in the formulation substudy, but it must be
met before enrollment in the main study (when applicable).
5. Patient (male or female) must be ≥ 18 years of age (except where age of majority is 16 years in a particular country, such as the United Kingdom).
6. Patient must have performance status ≤2 on the ECOG performance scale.
7. Patient must have an estimated life expectance of at least 3 months.
8. Patients must have adequate organ function as indicated by the following laboratory values:
• Platelets ≥ 75 x 109/L
• Absolute neutrophil count ≥ 1.5 x 109/L
• Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥60 mL/min
• Serum total bilirubin ≤ 1.5 mg/dL (unless documented Gilbert disease) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN)
• AST or ALT ≤ 5x ULN if secondary to liver metastases
9. For patients previously treated with myelosuppressive therapy, at least 3 weeks must have elapsed (6 weeks from prior chemotherapy if treated with mitomycin-C or a nitrosourea) and toxicity must have recovered to grade 1 or baseline) . For non-myelosuppressive therapy patients must have recovered from all treatment-related toxicities (to grade 1 or baseline) and have a treatment-free interval of at least 5 half -lives from prior non-biologic therapy and 1 half-life from prior biologic (e.g. antibody) therapy. Fourteen days must have elapsed since palliative radiation for bone metastasis; while radiation therapy for other indications requires a 4-week treatment-free interval.
10. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days of study enrollment. In addition, men and women must use adequate birth control for the duration of study participation and for 3 months after the last dose of study drug. Acceptable methods of contraception are described in Section 7.3. of the study protocol
11. The patient or his or her legal representative must be able to read, understand, and provide signed informed consent.
12. Patient is able to understand the study procedures and agrees to participate in the study by giving written informed consent. |
|
| E.4 | Principal exclusion criteria |
No new patients will be enrolled. Criteria previously used were as follows:
1. Patient has leukemia.
2. Patient is a pregnant or lactating female.
3. Patient has uncontrolled congestive heart failure, angina, or has had a myocardial infarction in the preceding 3 months.
4. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥ 2, atrial fibrillation of any grade, or QTc interval > 450 msec.
5. Patients with risk factors for Torsade de point (cardiac insufficiency New York Heart Association [NYHA II-IV], hypokalemia, hypomagnesemia, or hypocalcaemia, family history of long-QT syndrome) and patients receiving concomitant medication with QT-prolonging medicines.
6. Patient has an uncontrolled concurrent medical condition or disease, including but not limited to: active bleeding cirrhosis, or pancreatitis.
7. Patient has undergone bone marrow or stem cell transplantation in the past 6 months.
8. Patient has a known hypersensitivity to the components of TSR-011 or the excipients.
9. Patient has active or uncontrolled infection.
10. Patient has a known psychiatric or substance abuse disorder that would interfere with the requirements of this study.
11. Patient has active second primary malignancy (except cervical intraepithelial neoplasia, basal cell carcinoma of the skin).
12. Patient is observed to have a clinically active CNS metastases or carcinomatous meningitis. (Patients with CNS metastases with prior radiation who are on a stable dose of Glucocorticoids are eligible for participation in the Phase 1 cohort expansion and the Phase 2 part of thestudy.)
13. Patient has any other severe concurrent disease, which, in the judgment of the investigator, would preclude study participation.
14. Patient is known to be HIV+ or who has an AIDS-related illness.
15. Patient has a known history of or active (treated or not) Hepatitis B or C.
16. Patient has presence of ascites causing significant symptoms.
17. A patient must stop taking any prescription, over-the-counter, or herbal remedy known to be a strong inhibitor or inducer of CYP3A4/5 prior to the Screening period and should refrain from taking any known strong inhibitor or inducer of CYP3A4/5 over the course of the study. At his/her discretion, the Investigator may substitute another medication not considered to be a strong inhibitor or inducer of CYP3A4/5. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoints of Clinical Activity (not applicable as of the current protocol amendment):
-Overall tumor response as a function of ALK and TRK status
- PFS as a function of ALK and TRK status
- Response Rate as a function of ALK and TRK status
Pharmacokinetic Endpoints (not applicable as of the current protocol amendment):
- AUC: area under the plasma concentration-time curve
- AUCss: area under the plasma concentration-time curve at steady state
- Cmax: maximum plasma concentration
- Cmin: minimum plasma concentration
-Cmaxss: maximum plasma concentration at steady state
- Cminss: minimum plasma concentration at steady state
- CL/F: apparent oral clearance
- Vz/F: apparent volume of distribution |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Radiological assessment of overall tumour response will be performed at baseline of each treatment cycle.
Pharmacokinetic samples will be collected starting on Day 1 at the following time points: 0 hours (pre-dose), 1, 2, 4, 6, 8, 24, 48, and 72 hours post-dose and on Day 29 at the following time points: 0 hours
(pre-dose), 1, 2, 4, 6, 8, and 24 hours post-dose. Note: only the initial patient in a cohort will have this PK lead-in period until cohorts have converted to 3+3 design, at which point all patients in a cohort will
have a PK lead-in. In addition to Day 1 and 29, pre-dose (trough) PK samples will also be collected on Days 8 and 15, respectively |
|
| E.5.2 | Secondary end point(s) |
Exploratory Endpoints (not applicable as of the current protocol amendment):
- Assessment of pain
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessment of pain:
- Phase 1, Cycle 1: baseline, Days 8, 15, 29 and EOS
- Phase 1, Subsequent cycles: baseline, Day 29, every 8 weeks thereafter, EOS
- Phase 2a, Cycle 1: baseline, Days 8, 15, 29, and EOS
- Phase 2 a, Subsequent cycles: Day 29, every 8 weeks thereafter, EOS |
|
| 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 | No |
| 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 | 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) | 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 | 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Italy |
| Poland |
| Spain |
| Taiwan |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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 |
Print
