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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 (abound2L+)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Celgene
ClinicalTrials.gov Identifier:
NCT02250326
First received: September 24, 2014
Last updated: July 25, 2017
Last verified: July 2017
  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).

Condition Intervention Phase
Carcinoma, Non-Small-Cell Lung Drug: nab-paclitaxel IV Drug: CC-486 Drug: Duravalumab Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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+

Resource links provided by NLM:


Further study details as provided by Celgene:

Primary Outcome Measures:
  • Progression free survival [ Time Frame: Approximately 40 months ]
    To estimate the efficacy of each of the three treatments as second/third-line in NSCLC. Progression free survival (PFS) defined as 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 occurred first, based on the investigator's assessment of the data from CT scans using RECIST 1.1 guidelines. To explore the effect of treatment post initial progression, PFS defined by irRECIST criteria may be estimated for the subjects in the nab-paclitaxel/durvalumab arm. Baseline tumor measurements will be determined from the radiologic evaluation performed within 28 days before the start of study therapy.


Secondary Outcome Measures:
  • Adverse Events [ Time Frame: Approximately 40 months ]
    The safety/tolerability of the two treatment arms will be monitored through continuous reporting and evaluated by adverse events and serious adverse events, and incidence of subjects experiencing dose modifications, dose interruptions, and/or premature discontinuation of investigative product (IP). An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-existing condition) should be considered an AE.

  • Disease Control Rate [ Time Frame: Approximately 40 months ]
    Disease control rate is defined as the percent of subjects who have a radiologic complete response, partial response, or stable disease according to RECIST 1.1 guidelines, and irRECIST where applicable, as determined by the investigator.

  • Overall Survival [ Time Frame: Approximately 40 months ]
    Overall survival is defined as the time between randomization and death. All deaths, regardless of the cause of death, will be included. All subjects who are lost to follow-up prior to the end of the study or who are withdrawn from the study will be censored at the time of last contact. Subjects who are still receiving treatment as of the data cutoff date will be censored at the cutoff date. Overall survival will be analyzed in a similar model as that for PFS.

  • Overall Response Rate [ Time Frame: Approximately 40 months ]
    Overall response rate is defined as the percent of subjects who have a radiologic complete or partial response according to RECIST 1.1 guidelines, and irRECIST when applicable, as determined by the investigator.

  • Discontinuation rate [ Time Frame: Approximately 40 months ]
    The number and the percentage of subjects who discontinue study treatment will be presented based on the number of subjects who randomized into the study. Reasons for treatment discontinuation will be summarized for all subjects who discontinue study treatment during the treatment period.

  • Median dose intensity [ Time Frame: Approximately 40 months ]
    The dose intensity during the treatment period will be calculated separately for nab-Paclitaxel, CC-486 and durvalumab as the cumulative dose divided by the treatment duration in weeks. The descriptive statistics will be provided for the dose intensity by drug based on the treated population.

  • Incidence of dose reduction [ Time Frame: Approximately 40 months ]
    Dose reduction is defined as when the dose administered after Cycle 1 Day 1 is at a lower dose level than the dose the subject receives at the previous dosing visit. Number and percentage of subjects with at least 1 dose reduction, number of dose reductions, and reasons for reduction, by cycle and overall will be summarized separately for nab-Paclitaxel, CC-486 and durvalumab.

  • Progression free survival for combination treatment [ Time Frame: Approximately 40 months ]
    Estimate the relative efficacy of each of the combination therapy arms to the monotherapy arm: The Progression Free Survival (PFS) will be estimated by the hazard ratio (HR) and the associated two-sided 95% CIs using the stratified Cox proportional hazard model. To explore the effect of treatment post initial progression, PFS defined by irRECIST criteria may be estimated for the subjects in the nab-paclitaxel/durvalumab arm.

  • Progression free survival for monotherapy treatment [ Time Frame: Approximately 40 months ]
    The Progression Free Survival (PFS) will be estimated by the hazard ratio (HR) and the associated two-sided 95% CIs using the stratified Cox proportional hazard model. To explore the effect of treatment post initial progression, PFS defined by irRECIST criteria may be estimated for the subjects in the nab-paclitaxel/durvalumab arm.


Enrollment: 240
Actual Study Start Date: January 7, 2015
Estimated Study Completion Date: March 31, 2018
Primary Completion Date: July 17, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
Drug: nab-paclitaxel IV
nab-Paclitaxel intravenous (IV) infusion
Other Names:
  • Abraxane
  • ABI-007
Drug: CC-486
Oral CC-486
Other Names:
  • Oral AZA
  • Oral azacitidine
Experimental: 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
Drug: nab-paclitaxel IV
nab-Paclitaxel intravenous (IV) infusion
Other Names:
  • Abraxane
  • ABI-007
Experimental: 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
Drug: nab-paclitaxel IV
nab-Paclitaxel intravenous (IV) infusion
Other Names:
  • Abraxane
  • ABI-007
Drug: Duravalumab

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea, systemic lupus erythematosus, sarcoidosis syndrome, or Wegener's syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
    • Patients with vitiligo or alopecia
    • Patients with hypothyroidism (eg, following Hashimoto's syndrome) stable on hormone replacement
    • Any chronic skin condition that does not require systemic therapy
    • Patients without active disease in the last 5 years may be included but only after consultation with the study physician 28. 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) 29. 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.

      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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02250326

  Show 34 Study Locations
Sponsors and Collaborators
Celgene
Investigators
Study Director: Teng Jin Teng Jin Ong, MD Celgene
  More Information

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02250326     History of Changes
Other Study ID Numbers: ABI-007-NSCL-006
2014-001105-41 ( EudraCT Number )
Study First Received: September 24, 2014
Last Updated: July 25, 2017

Keywords provided by Celgene:
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

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Paclitaxel
Albumin-Bound Paclitaxel
Azacitidine
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Enzyme Inhibitors
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 21, 2017