| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Small 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| 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 determine whether the combination of alisertib + paclitaxel improves progression-free survival (PFS) compared with placebo + paclitaxel |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of the combination of alisertib + paclitaxel in small cell lung cancer (SCLC) patients
• To determine whether the combination of alisertib + paclitaxel improves overall survival (OS) compared with placebo + paclitaxel
• To determine whether the combination of alisertib + paclitaxel improves the overall response rate (ORR) compared with placebo + paclitaxel
• To determine whether the combination of alisertib + paclitaxel improves the disease control rate (DCR) compared with placebo + paclitaxel
• To determine whether the combination of alisertib + paclitaxel improves the duration of response (DOR) compared with placebo + paclitaxel
• To evaluate patient lung cancer associated symptoms of cough, dyspnea, and pain as measured by patient-reported outcome (PRO) instruments
• To measure plasma alisertib concentrations to contribute to population pharmacokinetic (PK) analysis
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients ≥ 18 years old.
2. Have a pathologically (histology or cytology) confirmed diagnosis of SCLC.
3. Have received and progressed after a platinum based standard chemotherapy regimen for first line treatment of SCLC, either limited stage (LS) or extensive stage (ES). Patients could not have received any prior second-line therapy for relapsed or progressive disease, including re-treatment with original frontline regimen. Patients should have relapsed within < 180 days after their response to first line therapy. At least 3 weeks should have elapsed between the end of first line therapy and the first dose of study drug. No previous irradiation to the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression.
4. Have measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) within ≤ 2 weeks before randomization. Clear radiographic evidence of disease progression after initial therapy should have been documented.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (PS 0 1).
6. Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed, provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids. Patients should be without neurologic dysfunction that would confound the evaluation of neurological and/or other AEs. Patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (eg, carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study. Use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed. Radiotherapy must have been completed a minimum of 14 days prior to randomization, and patients must have recovered from AEs related to the radiotherapy to < grade 1 (except alopecia).
7. Patients requiring full systemic anticoagulation are eligible if they have tolerated treatment with a stable dose and schedule without bleeding complications for more than 1 month.
8. Female patients who:
• Are postmenopausal for at least 1 year before the screening visit, OR
• Are surgically sterile, OR
• If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form (ICF) through 30 days after the last dose of study drug, or
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
• Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
9. The patient or the patient’s legal representative is able to provide written informed consent. 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.
10. Screening clinical laboratory values as specified below:
• Absolute neutrophil count (ANC) ≥ 1500/mm3, platelet count ≥ 100,000/mm3, and hemoglobin ≥ 9 g/dL
• Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN)
• Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 x the institutional ULN (< 5 x if liver function test elevations are due to liver metastases)
• Serum albumin ≥ the lower limit of normal (LLN)
• Creatinine < 1.5 x institutional ULN or estimated creatinine clearance using the Cockcroft-Gault formula ≥ 30 mL/minute for patients with creatinine levels above institutional limits
11. Stable medical condition, including the absence of acute exacerbations of chronic illnesses, serious infections, or major surgery within 4 weeks before randomization, and otherwise noted in other inclusion/exclusion criteria.
12. Suitable venous access for the conduct of blood sampling and intravenous administration of study treatments.
13. Recovered (ie, ≤ Grade 1 toxicity) from the reversible effects of prior anticancer therapy. |
|
| E.4 | Principal exclusion criteria |
1. Any prior therapy for second-line treatment of SCLC.
2. Patients who relapsed ≥ 180 days after their response to first-line treatment.
3. Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent, including alisertib in any setting or any other investigational agent in the relapsed setting.
4. Prior treatment with paclitaxel or any other taxane agent.
5. Known hypersensitivity to Cremophor® EL, paclitaxel, or its components.
6. Any comorbid condition or unresolved toxicity that would preclude administration of alisertib or weekly paclitaxel.
7. Prior history of ≥ Grade 2 neurotoxicity that is not resolved to ≤ Grade 1.
8. Patients with symptomatic and/or progressive brain metastases or with carcinomatous meningitis.
9. Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of alisertib and during study conduct. Major prohibited enzyme inducers include: phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine, and St. John’s wort.
10. Inability to swallow alisertib or other orally administered medications.
11. Requirement for administration of proton pump inhibitor (PPI), H2 antagonist, or pancreatic enzymes. Use of any PPI in either continued or intermittent use will be prohibited during the conduct of the study and patients must discontinue any use of PPI within 4 days prior to the first dose of alisertib.
12. Diagnosed with or treated for another malignancy within 3 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type may be enrolled in the study if they have undergone complete resection and no evidence of active disease is present.
13. Other severe acute or chronic medical or psychiatric condition(s), including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.
14. History of myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, any ongoing cardiac arrhythmias of Grade > 2, thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy) within 6 months before receiving the first dose of study drug. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed. Patients with a pacemaker may be enrolled in the study upon discussion with the project clinician.
15. Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C. Testing is not required in the absence of clinical findings or suspicion. Patients with prior allogeneic bone marrow or organ transplantation or with an active condition of chronic immune suppression are not eligible.
16. Infection requiring IV antibiotic therapy or other serious infection within 14 days before the first dose of study drug.
17. Patients who are lactating or have a positive serum pregnancy test.
18. Surgery within 3 weeks (or 2 weeks for a minor surgery) before study enrollment and not fully recovered to baseline or to a stable clinical status. Insertion of a vascular device is allowed.
19. Unwilling or unable to comply with the protocol or
cooperate fully with the investigator and site personnel. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is PFS |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS will be assessed every cycle of therapy for the first 6 months, and then every 2 cycles between Days 21 and 28
It is expected that the study will last approximately 22 months to reach the final analysis of the PFS endpoint for the maximum sample size (16 months of enrollment and 6 months of additional follow-up for PFS) |
|
| E.5.2 | Secondary end point(s) |
• Safety and tolerability
• OS
• ORR, including complete response rate (CRR)
• Disease control rate (DCR)
• Duration of response (DOR)
• Symptom score, time to symptom relief, percentage of patients experiencing symptom relief, and time to symptom progression (cough, dyspnea, and pain)
• Plasma alisertib concentration (ie, PK) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
safety- ongoing
Patients will be followed for OS every 2 months (± 2 weeks) until death events are obtained from approximately 80% of all patients in the ITT population or 14 months after last patient is randomized, whichever occurs first |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Belgium |
| Canada |
| France |
| Italy |
| Czech Republic |
| Germany |
| Hungary |
| Spain |
| Poland |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 22 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 22 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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