| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced non-small cell lung cancer (NSCLC). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced non-small cell lung cancer (NSCLC). |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-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 estimate the efficacy of nab-paclitaxel administered intravenously (IV) on Days 8 and 15 with epigenetic modifying therapy of CC-486 once daily (QD) on Days 1 to 14 every 21 days or nab-paclitaxel administered intravenously (IV) on Days 1 and 8 with immunotherapy of durvalumab administered IV on Day 15 every 21 days, and nab-paclitaxel monotherapy administered IV on Days 1 and 8 every 21 days as
second/third-line treatment for advanced NSCLC. |
|
| E.2.2 | Secondary objectives of the trial |
- To estimate the relative efficacy of each of the combination therapy arms to the
monotherapy arm.
- To evaluate the safety and tolerability of nab-paclitaxel administered intravenously (IV) on Days 8 and 15 with epigenetic modifying therapy of CC-486 once daily (QD) on Days 1 to 14 every 21 days, or nab-paclitaxel administered intravenously (IV) on Days 1 and 8 with immunotherapy of durvalumab administered IV on Day
15 every 21 days, and nab-paclitaxel monotherapy administered IV on Days 1 and 8 every 21 days as second/third-line treatment for advanced NSCLC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria to be randomized/assigned in the study:
1.Age ≥ 18 years the time of signing the Informed Consent Form (ICF).
2.Understand and voluntarily provide written informed consent prior to the conduct of any study related assessments/procedures.
3.Able to adhere to the study visit schedule and other protocol requirements
4.Histologically or cytologically confirmed advanced NSCLC who will receive study therapy as second- or third-line of treatment for advanced disease.
5.No other current active malignancy requiring anticancer therapy.
6.Radiographically documented measurable disease (defined by the presence of ≥ 1 radiographically documented measurable lesion).
7.One prior platinum-containing chemotherapy for metastatic or recurrent NSCLC unless patients are ineligible to receive it it or if disease progressed within 6 months of a platinumcontaining neoadjuvant/adjuvant regimen. Patients may have received no more than one line of chemotherapy; immunotherapy in prior line of treatment (first or second line) is allowed.
8.Absolute neutrophil count (ANC) ≥ 1500 cells/mm3.
9.Platelets ≥ 100,000 cells/mm3.
10.Hemoglobin (Hgb) ≥ 9 g/dL.
11.Aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT/serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × upper limit of normal range (ULN) or ≤ 5.0 × ULN if liver metastases.
12.Total bilirubin ≤ 1.5 ULN (unless there is a known history of Gilberts Syndrome).
13.Serum creatinine ≤ 1.5 x ULN, or calculated creatinine clearance ≥ 60 mL/min (if renal impairment is suspected 24-hour urine collection for measurement is required).
14.Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
15.Females of childbearing potential [defined as a sexually mature woman who (1) have not undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months)] must:
a.Have a negative pregnancy test (ß-hCG) as verified by the study doctor within 72 hours prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact.
b.Either commit to true abstinence* from heterosexual contact or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting investigational product (IP), during the study therapy (including dose interruptions), and for 3 months after discontinuation of study therapy.
Male subjects must:
a.Practice true abstinence* or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 6 months following IP discontinuation, even if he has undergone a successful vasectomy.
b.Refrain from semen or sperm donation while taking durvalumab and for at least 3
months after the last dose of durvalumab.
16.Females must abstain from breastfeeding during study participation and 3 months after IP discontinuation.
*True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]. |
|
| E.4 | Principal exclusion criteria |
1. Refractory to prior taxane therapy for advanced disease (use in adjuvant setting possible if no disease recurrence within 12 months)
2. Evidence of active brain metastases, including leptomeningeal involvement Antiepileptic treatment is permitted in the context of prophylaxis for seizures.
3. Only evidence of disease is non-measurable at study entry
4. Known activating mutations in EGFR
5. Known activating mutations in EML4-ALK.
6. Preexisting peripheral neuropathy Grade > 2.
7. Unresolved toxicity Grade ≥ 2 from previous anticancer therapy (with exceptions)
8. Venous thromboembolism within 1 month prior to Cycle 1 Day 1.
9. Current congestive heart failure (NYHA Class II-IV).
10. History of the following within 6 months prior to Cycle 1 Day 1: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, NYHA Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant ECG abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder.
11. Known hepatitis B or C virus infection, known history of HIV infection, or receiving immunosuppressive or myelosuppressive medications that would increase the risk of serious neutropenic complications, history of active primary immunodeficiency, active tuberculosis
12. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
13. History of interstitial lung disease, of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies. Any lung disease that may interfere with the detection or management of suspected drug-related pulmonary toxicity.
14. Clinically significant malabsorption syndrome, persistent diarrhea, or known sub-acute bowel obstruction > Grade 2, despite medical management.
15. Treatment with any chemotherapy, investigational product, biologic or hormonal therapy for cancer treatment within 28 days prior to signing the ICF.
16. History of or suspected allergy to any IP or their excipients.
17. Major surgical procedure within 28 days prior to the first dose of IP.
18. Currently enrolled in any other clinical protocol or investigational trial that involves administration of experimental therapy and/or therapeutic devices.
19. Any other clinically significant medical condition, psychiatric illness, and/or organ dysfunction that will interfere with the administration of IP according to this protocol or which, in the views of Investigator, preclude combination chemotherapy.
20. Any other malignancy within 5 years prior to randomization/treatment assignment, or advanced malignant hepatic tumors (with exceptions)
21. Radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting IP, and/or from whom ≥ 30% of the bone marrow was irradiated. Prior radiation therapy to target lesion permitted only if there has been clear progression of the lesion since radiation was completed.
22. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
23. Any medical condition that confounds the ability to interpret data from the study.
24. Female patients who are pregnant or breastfeeding or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab.
25. Male patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab and from screening to 6 months after the last dose of nab-paclitaxel.
26. History of allogenic organ transplantation.
27. Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment (with exceptions)
28. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab (with exceptions)
29. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
30. Prior enrollment and treatment in a previous durvalumab clinical study.
31. Patients who have received prior anti-PD-1 or anti PD-L1 :
- must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy;
- all prior AEs must have completely resolved or resolved to baseline prior to screening for this study;
- must not have experienced a Grade ≥ 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy;
- must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time from the date of randomization/treatment assignment to the date of disease progression or death (any cause) on or prior to the data cutoff date for analyses, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
- Disease control rate
- Overall response rate
- Overall survival
Safety
- The type, frequency, and severity of AEs and SAEs graded using National Cancer
Institute Common Terminology Criteria for Adverse Events (Version 4.0).
- Discontinuation rate
- The median dose intensity
- The incidence of dose reduction |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Disease control rate, OS, and ORR within and the difference between the nab-paclitaxel/CC-486 combination and nab-paclitaxel monotherapy treatment arms will be estimated at the time of the final analysis of the PFS endpoint when approximately 120 PFS events have been observed between these two arms. The same endpoints will be estimated within the nabpaclitaxel/durvalumab arm and between this and the nab-paclitaxel monotherapy arms when approximately 50 PFS events have been observed in the nab-paclitaxel/durvalumab arm. |
|
| 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 | No |
| 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 | Yes |
| 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) | 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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
| 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 | 27 |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| 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
|
The End of Trial is defined as either the:
- date of the last visit of the last subject to complete the post-treatment follow-up, or
- the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol.
The sponsor may consider closing this trial when data supporting key
endpoints and objectives of the study have been analyzed. |
|
| 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 | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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