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).
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
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.
- 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
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
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
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
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
22. Any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the
23. Any medical condition that confounds the ability to interpret data from the
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
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
- Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra
- 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
- 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.