A Phase 2, Open-Label, Multi-Center Study to Assess Safety and Efficacy of Second/Third-Line Treatment With NAB®-Paclitaxel (ABI-007) In Combination With Epigenetic Modifying Therapy Of CC-486, Or Immunotherapy of Durvalumab (MEDI4736), Or As Monotherapy In Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC): Abound.2L+
Overview
- Phase
- Phase 2
- Intervention
- nab-paclitaxel IV
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Sponsor
- Celgene
- Enrollment
- 240
- Locations
- 34
- Primary Endpoint
- Kaplan Meier Estimate of Progression-Free Survival (PFS) as Assessed by the Investigator
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a Phase 2, open-label, multicenter study to assess the efficacy and safety of second/third-line treatment with nab-paclitaxel in combination with the epigenetic modifying therapy of CC-486 or immunotherapy of durvalumab, and nab-paclitaxel monotherapy in subjects with advanced non-small cell lung cancer (NSCLC).
Detailed Description
This Phase 2 study will test the hypothesis that epigenetic modifying therapy of CC-486 or immunotherapy of durvalumab can improve the anti-tumor activity of nab-paclitaxel in subjects with advanced non-small cell lung cancer (NSCLC) who have received no more than one prior chemotherapy regimen for their advanced disease. It will further assess efficacy and safety of nab-paclitaxel monotherapy in this setting. Each subject will receive study therapy as second- or third-line of treatment. Approximately 240 male and female subjects with advanced NSCLC will be assigned to one of the following treatment arms (approximately 80 subjects per group): nab-paclitaxel /CC-486 combination therapy, nab-paclitaxel/durvalumab combination therapy or nab-paclitaxel monotherapy prior to receiving first dose of Investigational Product. A permuted-block randomization method will be employed to assign the subjects among the treatment arms that are enrolling simultaneously, when applicable, stratified by the following baseline factors: ECOG performance status (0 versus 1), gender (males versus females), and smoker (yes versus no). Treatment assignments of subjects to the nab-paclitaxel/CC-486 combination therapy and nab-paclitaxel monotherapy arms will be conducted completely in a randomized fashion.
Investigators
Eligibility Criteria
Inclusion Criteria
- •1.Age ≥ 18 years the time of signing the Informed Consent Form (ICF).
- •Understand and voluntarily provide written informed consent prior to the conduct of any study related assessments/procedures.
- •Able to adhere to the study visit schedule and other protocol requirements.
- •Histologically or cytologically confirmed advanced NSCLC who will receive study therapy as second- or third-line of treatment for advanced disease.
- •No other current active malignancy requiring anticancer therapy.
- •Radiographically documented measurable disease (defined by the presence of ≥ 1 radiographically documented measurable lesion).
- •One prior platinum-containing chemotherapy for metastatic or recurrent NSCLC unless patients are ineligible to receive it. Patients may have received no more than one line of chemotherapy; immunotherapy in prior line of treatment (first or second line) is allowed. Absolute neutrophil count (ANC) ≥ 1500 cells/mm
- •Platelets ≥ 100,000 cells/mm
- •Hemoglobin (Hgb) ≥ 9 g/dL.
- •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.
Exclusion Criteria
- •The presence of any of the following will exclude a subject from enrollment:
- •Refractory to prior taxane therapy for advanced disease. Prior taxane used in the adjuvant setting does not exclude eligibility, provided there is no disease recurrence within 12 months upon completion of chemotherapy in that setting.
- •Evidence of active brain metastases, including leptomeningeal involvement (prior evidence of brain metastasis are permitted only if asymptomatic and clinically stable for at least 8 weeks following completion of therapy). MRI of the brain (or CT scan w/contrast) is preferred.
- •Only evidence of disease is non-measurable at study entry.
- •Known activating EGFR mutations (such as exon 19 deletions or L858R).
- •Known activating EML4-ALK mutations.
- •Preexisting peripheral neuropathy of Grade \> 2 (per NCI CTCAE v4.0).
- •Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
- •Venous thromboembolism within 1 month prior to Cycle 1 Day
- •Current congestive heart failure (New York Heart Association Class II-IV).
Arms & Interventions
Combination arm: nab-paclitaxel and CC-486
Subjects in the combination arm will receive nab-paclitaxel 100 mg\^/m2 intravenous (IV) infusion over 30 minutes on Days 8 and 15 and CC-486 200 mg orally daily (QD) on Days 1 to14 of each 21-day treatment cycle
Intervention: nab-paclitaxel IV
Combination arm: nab-paclitaxel and CC-486
Subjects in the combination arm will receive nab-paclitaxel 100 mg\^/m2 intravenous (IV) infusion over 30 minutes on Days 8 and 15 and CC-486 200 mg orally daily (QD) on Days 1 to14 of each 21-day treatment cycle
Intervention: CC-486
Monotherapy arm: nab-paclitaxel IV infusion
Subjects in the monotherapy arm will receive nab-Paclitaxel 100 mg/m\^2 IV infusion over 30 minutes on Days 1 and 8 of each 21-day treatment cycle
Intervention: nab-paclitaxel IV
Nab-paclitaxel and Durvalumab combination
subjects in the nab-Paclitaxel/durvalumab combination arm will receive nab-Paclitaxel 100 mg/m2 IV infusion over 30 minutes on Days 1 and 8 and durvalumab 1125 mg IV infusion over approximately 1 hour on Day 15 of each 21-day treatment cycle
Intervention: nab-paclitaxel IV
Nab-paclitaxel and Durvalumab combination
subjects in the nab-Paclitaxel/durvalumab combination arm will receive nab-Paclitaxel 100 mg/m2 IV infusion over 30 minutes on Days 1 and 8 and durvalumab 1125 mg IV infusion over approximately 1 hour on Day 15 of each 21-day treatment cycle
Intervention: Duravalumab
Outcomes
Primary Outcomes
Kaplan Meier Estimate of Progression-Free Survival (PFS) as Assessed by the Investigator
Time Frame: From date of first dose of IP to DP; up to data cut-off date of 30 August (Aug) 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 December (Dec) 2017 for Durva + nab-paclitaxel; participants were followed for PFS for up to 18 months
Progression-free survival was defined as the time in months from the date of randomization/assignment to the date of disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria documented by computed tomography (CT) scan, not including symptomatic deterioration, or death (any cause) on or prior to the clinical cut-off date, which ever occurred earlier. Participants who did not have disease progression and had not died, regardless of whether they were discontinued from treatment, were censored at the date of last tumor assessment, on or prior to the clinical cut-off date that the participant was progression free. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions from nadir.
Secondary Outcomes
- Percentage of Participants Who Achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) According to RECIST V 1.1 Criteria(Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel)
- Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response According to RECIST V 1.1 Criteria(Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel)
- Kaplan Meier Estimate of Overall Survival (OS)(Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; participants were followed for overall survival up to 30 months)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Entire Treatment Period(TEAEs were collected up to 4 weeks after receiving last dose of investigational product (IP) for nab-paclitaxel and CC-486 + nab-paclitaxel, and up to 90 days after the last IP dose for Durva + nab-paclitaxel; TEAEs were collected up to 354 weeks)
- Percentage of Participants Who Discontinued Study Treatment(Up to 30 Aug 2017 for CC-486 + nab-paclitaxel and 26 Nov 2019 for nab-paclitaxe and 20 Jul 2023 for Durva + nab-paclitaxel (up to 445 weeks))
- Dose Intensity Per Week of Nab-Paclitaxel(Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel)
- Dose Intensity Per Week of CC-486(Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel)
- Dose Intensity Per Week of Durvalumab(Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel)
- Percentage of Participants With Study Drug Dose Reductions(Up to 16 Jan 2017 for CC-486 + nab-paclitaxel and up to 26 Nov 2019 for nab-paclitaxel and Durva + nab-paclitaxel (up to 255 weeks))