Clinical Trials /

Safety and Efficacy Study of Nab®-Paclitaxel With CC-486 or Nab®-Paclitaxel With Durvalumab, and Nab®-Paclitaxel Monotherapy as Second/Third-line Treatment for Advanced Non-small Cell Lung Cancer

NCT02250326

Description:

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).

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy Study of Nab®-Paclitaxel With CC-486 or Nab®-Paclitaxel With Durvalumab, and Nab®-Paclitaxel Monotherapy as Second/Third-line Treatment for Advanced Non-small Cell Lung Cancer
  • Official Title: 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+

Clinical Trial IDs

  • ORG STUDY ID: ABI-007-NSCL-006
  • SECONDARY ID: 2014-001105-41
  • NCT ID: NCT02250326

Conditions

  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
nab-paclitaxel IVAbraxane, ABI-007Combination arm: nab-paclitaxel and CC-486
CC-486Oral AZA, Oral azacitidineCombination arm: nab-paclitaxel and CC-486
DuravalumabNab-paclitaxel and Durvalumab combination

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Combination arm: nab-paclitaxel and CC-486ExperimentalSubjects 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
  • nab-paclitaxel IV
  • CC-486
Monotherapy arm: nab-paclitaxel IV infusionExperimentalSubjects 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
  • nab-paclitaxel IV
Nab-paclitaxel and Durvalumab combinationExperimentalsubjects 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
  • nab-paclitaxel IV
  • Duravalumab

Eligibility Criteria

        Inclusion Criteria: 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. 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/mm3.

        8. Platelets ≥ 100,000 cells/mm3. 9. Hemoglobin (Hgb) ≥ 9 g/dL. 10. 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.

        11. Total bilirubin ≤ 1.5 ULN (unless there is a known history of Gilberts Syndrome).

        12. 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).

        13. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 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:

          1. 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.

          2. Either commit to true abstinence* from heterosexual contact (which must be reviewed on
             a monthly basis) 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:

          1. 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.

          2. 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.

             Exclusion Criteria:

               -  The presence of any of the following will exclude a subject from enrollment:

                    1. 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.

                    2. 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.

                    3. Only evidence of disease is non-measurable at study entry.

                    4. Known activating EGFR mutations (such as exon 19 deletions or L858R).

                    5. Known activating EML4-ALK mutations.

                    6. Preexisting peripheral neuropathy of Grade > 2 (per NCI CTCAE v4.0).

                    7. 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.

                    8. Venous thromboembolism within 1 month prior to Cycle 1 Day 1.

                    9. Current congestive heart failure (New York Heart Association Class II-IV).

                   10. History of the following within 6 months prior to Cycle 1 Day 1: a
                       myocardial infarction, severe/unstable angina pectoris, coronary/peripheral
                       artery bypass graft, New York Heart Association (NYHA) Class III-IV heart
                       failure, uncontrolled hypertension, clinically significant cardiac
                       dysrhythmia or clinically significant electrocardiogram (ECG) abnormality,
                       cerebrovascular accident, transient ischemic attack, or seizure disorder.

                   11. Known hepatitis B or C virus (HBV/HCV) infection, known history of human
                       immunodeficiency virus (HIV) infection, or receiving immunosuppressive or
                       myelosuppressive medications that would in the opinion of the investigator,
                       increase the risk of serious neutropenic complications, history of active
                       primary immunodeficiency, active tuberculosis (clinical evaluation that
                       includes clinical history, physical examination and radiographic findings,
                       and TB testing in line with local practice).

                   12. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring
                       systemic therapy, defined as ongoing signs/symptoms related to the infection
                       without improvement despite appropriate antibiotics, antiviral therapy,
                       and/or other treatment.

                   13. History of interstitial lung disease, history of slowly progressive dyspnea
                       and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary
                       fibrosis, or pulmonary hypersensitivity pneumonitis or multiple allergies.
                       Any lung disease that may interfere with the detection or management of
                       suspected drug-related pulmonary toxicity.

                   14. Subject has a clinically significant malabsorption syndrome, persistent
                       diarrhea, or known sub-acute bowel obstruction > NCI CTCAE 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. Concurrent use of hormonal therapy for non-cancer-related conditions
                       (e.g. hormone replacement therapy) is acceptable.

                   16. History of or suspected allergy to any IP or their excipients.

                   17. Major surgical procedure (as defined by the Investigator) within 28 days
                       prior to the first dose of IP. Note: Local surgery of isolated lesions for
                       palliative intent is acceptable.

                   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 the
                       therapy 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
                       assignement, or advanced malignant hepatic tumors, with the exception of
                       adequately treated squamous cell carcinoma of the skin, in-situ carcinoma of
                       the cervix, uteri, non-melanomatous skin cancer, carcinoma in situ of the
                       breast, or incidental histological finding of prostate cancer (TNM
                       Classification of Malignant Tumours (TNM) stage of T1a or T1b). (All
                       treatment of which should have been completed 6 months prior to signing
                       ICF).

                   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 a target lesion is 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 screenin to 90 days after the last dose of
                       durvalumab and from screening to 6 months after the last dose of of
                       nab-paclitaxel.

                   26. History of allogenic organ transplantation.

                   27. Current or prior use of immunosuppressive medication within 14 days before
                       the first dose of durvalumab. The following are exceptions to this
                       criterion:

               -  Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra
                  articular injection)

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or its equivalent

               -  Steroids as premedication for hypersensitivity reactions (eg, CT scan
                  premedication) 28. Receipt of live attenuated vaccine within 30 days prior to the
                  first dose of IP. Note: Patients, if enrolled, should not receive live vaccine
                  during the study and up to 30 days after the last dose of IP.

                  29. Prior enrollment and treatment in a previous durvalumab clinical study. 30.
                  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 AEs while receiving prior immunotherapy 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. NOTE:
                  Subjects with endocrine AE of ≤ Grade 2 are permitted to enroll if they are
                  stably maintained on appropriate replacement therapy and are asymptomatic.

               -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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 Outcome Measures

Measure:Percentage of Participants Who Achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) According to RECIST V 1.1 Criteria
Time Frame: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
Safety Issue:
Description:Disease control rate was defined as the percentage of participants who had a CR, PR or SD during the course of the study, according to RECIST version 1.1 criteria, as evaluated by the investigator. RECIST Version 1.1 criteria is defined as follows: Complete Response is the disappearance of all target lesions; Partial Response is at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. Responses were evaluated every 6 weeks.
Measure:Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response According to RECIST V 1.1 Criteria
Time Frame: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
Safety Issue:
Description:Overall Response was defined as percentage of participants who achieved a radiologic confirmed complete response or partial response according to RECIST V 1.1 criteria and compared with baseline among all tumor assessments, where baseline was the last CT obtained prior to or on Day 1 of treatment. Per RECIST V 1.1 criteria, a CR is defined as a disappearance of all target lesions; a PR is defined as having at least a 30% decrease in the sum of diameters of target lesions from baseline. Responses were evaluated every 6 weeks.
Measure:Kaplan Meier Estimate of Overall Survival (OS)
Time Frame: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
Safety Issue:
Description:Overall survival was defined as the time in months between randomization/treatment assignment and death from any cause. Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off, whichever was earlier. Participants who were lost to follow-up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact.
Measure:Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Entire Treatment Period
Time Frame:TEAEs were collected up to 4 weeks after receiving last dose of 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 86.1 weeks
Safety Issue:
Description:TEAEs were defined as any adverse event or serious adverse event that occurred or worsened on or after the day of the first dose of the IP through 28 days after the last dose of IP for Arms A and C or up to 90 days after the last dose for Arm B, and those SAEs made known to the investigator at any time thereafter that are suspected of being related to IP. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild l intervention/therapy required Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death.
Measure:Percentage of Participants Who Discontinued Study Treatment
Time Frame: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
Safety Issue:
Description:The discontinuation rate was defined as the percentage of participants who had study drug discontinued and was assessed throughout the conduct of the study.
Measure:Dose Intensity Per Week of Nab-Paclitaxel
Time Frame: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
Safety Issue:
Description:Dose intensity was the cumulative dose divided by the dosing period in weeks.
Measure:Dose Intensity Per Week of CC-486
Time Frame: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
Safety Issue:
Description:Dose intensity was the cumulative dose divided by the dosing period in weeks.
Measure:Dose Intensity Per Week of Durvalumab
Time Frame: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
Safety Issue:
Description:Dose intensity was the cumulative dose divided by the dosing period in weeks).
Measure:Percentage of Participants With Study Drug Dose Reductions
Time Frame:Up to 16 Jan 2017 for CC-486 + nab-paclitaxel and up to 23 Dec 2017 for nab-paclitaxel and 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
Safety Issue:
Description:A dose reduction occurred when the dose assigned at a visit was lower than the dose assigned at the previous visit. Dose reductions were typically caused by clinically significant laboratory abnormalities and/or TEAEs or toxicities.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Cancer of the lung
  • lung neoplasm
  • NSCLC - non-small cell lung cancer
  • Nonsquamou
  • squamous
  • squamous NSCLC
  • Tumor
  • locally advanced NSCLC
  • metastatic NSCLC
  • advanced lung cancer
  • metastatic lung cancer
  • non-squamous NSCLC
  • lung cancer
  • Abraxane
  • ABI-007
  • nab-paclitaxel
  • albumin-bound paclitaxel
  • taxanes
  • CC-486
  • oral azacitidine
  • azacitidine
  • second line treatment of lung cancer
  • second line treatment
  • Celgene
  • abound.2L
  • third line treatment
  • durvalumab
  • immunotherapy
  • MEDI4736

Last Updated

May 5, 2021