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
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: nab-paclitaxel IV; CC-486; Duravalumab
Intervention description: nab-Paclitaxel intravenous (IV) infusion; Oral CC-486
Intervention MeSH terms: Paclitaxel; Azacitidine; Cc-486
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 240.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
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

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).
    

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.