| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ALK positive Locally Advanced or Metastatic Non-small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic or locally advanced non-small cell lung cancer |
|
| 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 | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To compare the efficacy of brigatinib to that of alectinib in patients with ALK+ locally advanced or metastatic NSCLC who have progressed on crizotinib as evidenced by PFS as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy of brigatinib with that of alectinib as evidenced by overall survival (OS), PFS as assessed by the investigator, ORR, DOR, and time to response (all as assessed by RECIST v1.1).
2. To compare the efficacy of brigatinib in the CNS to that of alectinib as evidenced by iORR, iDOR, and time to iPD as assessed by modified RECIST criteria.
3. To assess the safety and tolerability of brigatinib in comparison with alectinib.
4. To collect plasma concentration-time data for brigatinib to contribute to population pharmacokinetic (PK) analyses.
5. To assess patient-reported symptoms and health-related quality of life (HRQoL) with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (v3.0) and its Quality of Life Lung Cancer Module (QLQ-LC13), in patients treated with brigatinib compared with those treated with alectinib.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, patients aged 18 years or older or of local legal adult age.
2. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
3. Have histologically or cytologically confirmed stage IIIB (locally advanced or recurrent) or stage IV NSCLC.
4. Must meet one of the following criteria:
a) Have documentation of ALK rearrangement by a positive result from the Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit or the Ventana ALK (D5F3) CDx Assay or Foundation Medicine’s FoundationOne CDx.
b) Have documented ALK rearrangement by a different test and be able to provide tumor sample to the central laboratory. (Note: central laboratory ALK rearrangement testing results are not required to be obtained before randomization.)
5. Had PD while on crizotinib, as assessed by the investigator or treating physician. (Note: crizotinib does not need to be the last therapy a patient received. The patient may have received chemotherapy as his/her last therapy.)
6. Treatment with crizotinib for at least 4 weeks before progression.
7. Have had no other ALK inhibitor other than crizotinib.
8. Have had no more than 2 prior regimens of systemic anticancer
therapy (other than crizotinib) in the locally advanced or metastatic setting*.
Note: a systemic anticancer therapy regimen will be counted if it is
administered over for at least 1 complete cycle. A new anticancer agent used as maintenance therapy will be counted as a new regimen.
Neoadjuvant or adjuvant systemic anticancer therapy will be counted as a prior regimen if disease progression/recurrence occurred within 12 months upon completion of this neoadjuvant or adjuvant therapy.
*Systemic therapy followed by maintenance therapy will be considered as one regimen if the maintenance therapy consists of a drug or drugs that were used in the regimen that immediately preceded maintenance.
9. Have at least 1 measurable (ie, target) lesion per RECIST v1.1.
10. Have recovered from toxicities related to prior anticancer therapy to NCI CTCAE v4.03 grade ≤1. (Note: treatment-related alopecia or peripheral neuropathy that are grade >1 are allowed, if deemed irreversible.)
11. Have adequate organ function, as determined by:
a) Total bilirubin ≤1.5 times the upper limit of normal (ULN).
b) Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2, using the modification of diet in renal disease equation.
c) Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤2.5 × ULN; ≤5 × ULN is acceptable if liver metastases are present.
d) Serum lipase ≤1.5 × ULN.
e) Platelet count ≥75 ×109/L.
f) Hemoglobin ≥9 g/dL.
g) Absolute neutrophil count ≥1.5 × 109/L.
12. Suitable venous access for study-required blood sampling (ie, including PK and laboratory safety tests).
13. Have the willingness and ability to comply with scheduled visits and study procedures.
14. For female patients of childbearing potential, have a negative
pregnancy test documented before randomization.
15. Female patients of childbearing potential and male patients with partners of childbearling potential must agree to use a highly effective nonhormonal form of contraception with their sexual partners during the dosing period and for a period of at least 120 days after the end of treatment with either brigatinib or alectinib.
16. Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a) Agree to practice one highly effective nonhormonal method of contraception (see Appendix F) from the time of signing the informed consent through 120 days after the last dose of study drug, or
b) Agree to practice sexual abstinence, or,
c) Do not donate semen or sperm during treatment and for 120 days after the last dose of study therapy (120 days is the maximum reported duration of the process of human spermatogenesis).
17. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
(Note: Given that, globally, the patient population who has received crizotinib as the sole ALK inhibitor is decreasing, Takeda reserves the right to amend the inclusion criteria to include crizotinib intolerant patients and/or patients who have progressed on or been found intolerant to ALK inhibitors other than crizotinib, brigatinib, or alectinib.)
|
|
| E.4 | Principal exclusion criteria |
1. Participation in the control (crizotinib) arm of Study AP26113-13-301 (ALTA 1L).
2. Received crizotinib within 7 days before randomization.
3. Have a history or presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis.
4. Have uncontrolled hypertension. Patients with hypertension should beunder treatment for control of blood pressure upon study entry.
5. Received systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers within 14 days before randomization.
6. Treatment with any investigational systemic anticancer agents within 14 days or 5 half-lives, whichever is longer, before randomization.
7. Have been diagnosed with another primary malignancy other than NSCLC, except for adequately treated nonmelanoma skin cancer or cervical cancer in situ; definitively treated nonmetastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the
other primary malignancy.
8. Received chemotherapy or radiation therapy within 14 days before randomization except for stereotactic radiosurgery (SRS) or stereotactic body radiation therapy.
9. Received anticancer monoclonal antibodies within 30 days of randomization.
10. Had major surgery within 30 days of randomization. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed.
11. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening (patients with asymptomatic brain metastases or patients who have stable symptoms and did not require an increased dose of corticosteroids to control symptoms within 7 days before randomization will be enrolled). Note: If a patient has worsening neurological
symptoms or signs due to CNS metastasis, the patient needs to complete local therapy and be neurologically stable (with no requirement for an increasing dose of corticosteroids or use of anticonvulsants) for at least 7 days before randomization.
12. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging). Patients with leptomeningeal disease and without cord compression are allowed.
13. Have significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to the following:
a) Myocardial infarction within 6 months before randomization.
b) Unstable angina within 6 months before randomization.
c) New York Heart Association Class III or IV heart failure within 6 months before randomization.
d) History of clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the treating physician.
e) Any history of clinically significant ventricular arrhythmia.
14. Had cerebrovascular accident or transient ischemic attack within 6 months before first dose of study drug.
15. Have malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the study drug.
16. Have an ongoing or active infection, including but not limited to, the requirement for intravenous antibiotics.
17. Have a known history of HIV infection. Testing is not required in the absence of history.
18. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection. Testing is not required in the absence of history.
19. Any serious medical condition or psychiatric illness that could, in the investigator's opinion, potentially compromise patient safety or interfere with the completion of treatment according to this protocol.
20. Have a known or suspected hypersensitivity to brigatinib or alectinib or their excipients.
21. Life-threatening illness unrelated to cancer.
22. Female patients who are lactating and breastfeeding.
23. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is progression free survival (PFS) as assessed by the blinded Independent Review Committee (BIRC) per RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time interval from the date of randomization until the first date at which disease progression is objectively documented by RECIST, or death due to any cause.
The interim analysis will be preformed after the first 115 events have been observed; the final analysis will be preformed after 164 events have been observed |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints:
_OS
Other secondary endpoints:
1. PFS, as assessed by the investigator per RECIST v1.1.
2. ORR, as assessed by the investigator and BIRC per RECIST v1.1.
3. DOR as assessed by the investigator and BIRC.
4. Time to response, as assessed by the investigator and BIRC.
5. iORR, as assessed by BIRC per modified RECIST v1.1 (as described in protocol and BIRC charter).
6. iDOR, as assessed by the BIRC per modified RECIST v1.1.
7. Time to iPD as assessed by the BIRC per modified RECIST v1.1
8. HRQoL assessed with the global health status/quality of life and other function and symptom domains from EORTC QLQ-C30 (v3.0) and EORTC QLQ-LC13. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| For the key secondary endpoints formal statistical tests will be performed only once, when PFS per BIRC is statistically significant. |
|
| 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 | No |
| 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) | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 56 |
| 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 |
| Argentina |
| Chile |
| Hong Kong |
| Taiwan |
| Brazil |
| Canada |
| China |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Thailand |
| United States |
| Austria |
| Croatia |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Romania |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
Death of the last study subject or 3 years after the last subject started study treatment, which ever comes first.
The sponsor may also terminate the study prematurely due to safety or administration reasons. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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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