A Phase I Trial of Combination Nab-Paclitaxel and Nintedanib or Nab-paclitaxel and Placebo in Relapsed Non-Small Cell Lung Cancer Adenocarcinoma
Overview
- Phase
- Phase 1
- Intervention
- Vargatef
- Conditions
- NSCLC, Recurrent
- Sponsor
- Royal Marsden NHS Foundation Trust
- Primary Endpoint
- Part 1: Maximum Tolerated Dose
- Status
- Withdrawn
- Last Updated
- 5 years ago
Overview
Brief Summary
A PHASE I/II TRIAL OF COMBINATION NAB-PACLITAXEL AND NINTEDANIB OR NAB-PACLITAXEL AND PLACEBO IN RELAPSED NSCLC ADENOCARCINOMA
Detailed Description
The study is divided into 2 parts: Part 1 is the Phase Ib portion of the trial and Part 2 is the Phase II portion of the trial. Once the Trial Steering Committee has completed the dose limiting toxicity (DLT) assessment for Part 1 and confirmed RP2D for Part 2, Part 2 enrolment will proceed. The objective(s) for each part are as follows: Part 1: The objective of Part 1 is to evaluate the safety and tolerability of combination nab-paclitaxel and nintedanib in patients with stage IIIb and IV adenocarcinoma of the lung in second and third treatment line setting and to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of nintedanib when given with nab-paclitaxel at 100mg/m2 d1, d8 q21. Part 2: The primary objective of Part 2 is to explore the efficacy of combination nab-paclitaxel and nintedanib versus nab-paclitaxel and placebo in the same patient population, with nintedanib/placebo given at the recommended phase 2 dose (RP2D) as defined during part 1 of the study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male or female patients aged 18 or over.
- •Patients with a pathologically confirmed diagnosis of stage IIIb or stage IV adenocarcinoma of the lung; patients with locally recurrent disease (stage IIIa) and no radical treatment options are also eligible.
- •Patients who have previously received no more than 2 lines of systemic therapy for NSCLC with palliative intent:
- •Chemotherapy as first or second line with palliative intent
- •Relapsing within 6 months of adjuvant chemotherapy after surgery or as part of radical chemo-radiotherapy, which count as one line of therapy
- •Licenced or experimental maintenance therapy is allowed (e.g. pemetrexed)
- •Immunotherapy at prior line of treatment (first or second line) is allowed.
- •Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-
- •Patients with estimated life expectancy of ≥ 12 weeks.
- •Patients with at least one radiologically measurable tumour lesion as defined by RECIST 1.1 criteria.
Exclusion Criteria
- •Patients with a known EGFR kinase sensitising mutation or ALK gene fusion prior to enrolment who have not received prior TKI (patients enrolled and subsequently found to be positive will remain on protocol). Patients with known EGFR activating mutation or ALK fusion who have received appropriate TKI treatment will be allowed.
- •Any concurrent anticancer systemic therapy.
- •Prior treatment with nintedanib or any other VEGFR inhibitor; prior treatment with bevacizumab is allowed
- •Patients 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.
- •Inadequate laboratory parameters defined by:
- •Absolute neutrophil count (ANC) \< 1,500/μl (1.5x109/L).
- •Platelets \< 100,000/μl (100x109/L).
- •Haemoglobin \< 9.0 g/dl or requiring transfusions.
- •Creatinine clearance \< 45 ml/min (by local institutional methods).
- •Total bilirubin outside normal limits:
Arms & Interventions
Part 1: (Phase Ib) Dose Escalation
A dose-finding study of nintedanib (Vargatef) with nab-paclitaxel (Abraxane) with a standard 3+3 design. In the dose escalation part there will be 3 dose cohorts of nintedanib: Dose level -1: 100mg po BID d2-7, 9-21, q21 Dose level 1: 150mg po BID d2-7, 9-21, q21 Dose level 2: 200mg po BID d2-7, 9-21, q21
Intervention: Vargatef
Part 1: (Phase Ib) Dose Escalation
A dose-finding study of nintedanib (Vargatef) with nab-paclitaxel (Abraxane) with a standard 3+3 design. In the dose escalation part there will be 3 dose cohorts of nintedanib: Dose level -1: 100mg po BID d2-7, 9-21, q21 Dose level 1: 150mg po BID d2-7, 9-21, q21 Dose level 2: 200mg po BID d2-7, 9-21, q21
Intervention: Abraxane
Part 1: Dose Expansion
In the dose expansion part, 6 additional patients will be enrolled at the maximum tolerated dose (MTD) of nintedanib (Vargatef) with nab-paclitaxel (Abraxane), prior to proceeding to part 2.
Intervention: Vargatef
Part 1: Dose Expansion
In the dose expansion part, 6 additional patients will be enrolled at the maximum tolerated dose (MTD) of nintedanib (Vargatef) with nab-paclitaxel (Abraxane), prior to proceeding to part 2.
Intervention: Abraxane
Part 2: (Phase II)
A placebo-controlled, randomised, double-blind, 2-arm, phase 2 multi-centre clinical trial of nab-paclitaxel (Abraxane) with nintedanib (Vargatef) and nab-paclitaxel alone. Arm A: nab-paclitaxel + placebo Arm B: nab-paclitaxel + nintedanib
Intervention: Vargatef
Part 2: (Phase II)
A placebo-controlled, randomised, double-blind, 2-arm, phase 2 multi-centre clinical trial of nab-paclitaxel (Abraxane) with nintedanib (Vargatef) and nab-paclitaxel alone. Arm A: nab-paclitaxel + placebo Arm B: nab-paclitaxel + nintedanib
Intervention: Abraxane
Part 2: (Phase II)
A placebo-controlled, randomised, double-blind, 2-arm, phase 2 multi-centre clinical trial of nab-paclitaxel (Abraxane) with nintedanib (Vargatef) and nab-paclitaxel alone. Arm A: nab-paclitaxel + placebo Arm B: nab-paclitaxel + nintedanib
Intervention: placebo
Outcomes
Primary Outcomes
Part 1: Maximum Tolerated Dose
Time Frame: 1 and 2 years from patients commencement
To define Maximum tolerated dose (MTD) and evaluate incidence of dose-limiting toxicities (DLTs) during Cycle 1
Secondary Outcomes
- Part 1 and 2: Adverse Events Review(4 years from Start date of trial)
- Part 1 and 2: RECIST Response(4 years from start date of trial)
- Cycles Tolerated(4 years from start date of trial)
- Part 2: Overall Survival(9 months post Chemotherapy)