This is an open-label, non-randomized phase II trial of durvalumab in combination with
platinum-based doublet chemotherapy. Patients with stage IV NSCLC with HIV (cohort 1) or
HBV/HCV (cohort 2) infection will be eligible. Patients will receive standard chemotherapy
plus durvalumab (1500 mg Q3W) every three weeks for 4 cycles, followed by maintenance
treatment with durvalumab (1500 mg Q4W; with or without pemetrexed for non-squamous NSCLC per
the discretion of the investigator).
Patient will be enrolled into the trial using an optimal two-stage phase II trial design. If
0 of the 7 achieved a response, no further patients will be enrolled in that cohort. If 1 or
more of the first 7 patients has a response, accrual would continue until a total of 18
patients have been enrolled in that cohort. Objective response will be evaluated using the
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Safety and tolerability will be
evaluated by assessing the incidence of treatment-related grade 3 or higher AEs.
Treatment-related grade 3 or higher AEs will be defined as any grade 3 or higher AEs that
occur during the first 42 days of treatment and are related to the study treatment. AEs will
be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Subjects will receive 4 cycles of combination treatment: durvalumab (1500 mg every 3 weeks)
in combination with platinum-based doublet chemotherapy. The platinum-based doublet
chemotherapies (carboplatin plus paclitaxel/nab-paclitaxel vs. pemetrexed plus
carboplatin/cisplatin) are dependent on the tumor histology of the subject (squamous vs.
non-squamous). Only subjects who achieve stable disease or better radiological response after
4 cycles of induction treatment will be eligible to continue study treatment in maintenance.
The choice to treat non-squamous subjects with pemetrexed maintenance after the 4 induction
cycles will be determined by the investigator.
Inclusion Criteria:
1. Patients with stage IV NSCLC who had undergone no previous systemic therapy for stage
IV disease.
2. Cohort 1: Patients with HIV must be on an effective combination anti-retroviral
therapy (cART) regimen for ≥ 4 weeks Cohort 2: Patients with chronic HBV infection
will be eligible. Patients with positive hepatitis B core antibody (anti-HBc) but
negative surface antigen (HBsAg) will be eligible. Those with detectable HBV DNA who
are negative for HBsAg will also be eligible. For hepatitis C, patients with
detectable HCV RNA will be eligible. Those who have completed antiviral therapy for
HCV and undetectable HCV RNA will also be eligible.
3. Age > 18 years at time of study entry.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
5. Body weight >30kg
6. Adequate normal organ and marrow function as defined below:
- Hemoglobin ≥ 9.0 g/dL
- Absolute neutrophil count (ANC) ≥ 1,000 per mm3
- Platelet count ≥ 100,000 per mm3
- CD4 T-cell count ≥ 100 per mm3 for HIV-infected patients
- Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with their
physician.
- AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver
metastases are present, in which case it must be ≤5x ULN
- Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40
mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour
urine collection for determination of creatinine clearance:
Males: Creatinine CL (mL/min) = [Weight (kg) x (140 - Age)] / [72 x serum creatinine
(mg/dL)] Females: Creatinine CL (mL/min) = [Weight (kg) x (140 - Age) x 0.85] / [72 x
serum creatinine (mg/dL)]
7. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy).
8. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
9. Must have a life expectancy of at least 12 weeks.
Exclusion Criteria:
1. Sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q)
and/or ALK translocations by locally approved laboratory testing including blood-based
liquid biopsy.
2. Coinfection of HIV + HBV or HIV + HCV (coinfection of HIV and HCV allowed if HCV is
cured). Coinfection of HBV and HCV is allowed if otherwise eligible.
3. No measurable disease.
4. Receipt of the last dose of anticancer therapy (chemotherapy, targeted therapy) ≤ 21
days prior to the first dose of study treatment.
5. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy
(chemotherapy, targeted therapy, radiation therapy) with the exception of alopecia,
vitiligo, and the laboratory values defined in the inclusion criteria.
6. Patients who have had whole brain radiation therapy (WBRT) during the previous 2 weeks
before treatment (no washout period is required for patients who have received
stereotactic body radiation therapy).
7. Subject has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic)
within 4 weeks prior to starting study drug or has not recovered from side effects of
such procedure (≥ grade 2 AE related to such procedure). Video-assisted thoracic
surgery (VATS) and mediastinoscopy will not be counted as major surgery and subject
can be enrolled in the study ≥ 1 week after the procedure.
8. History of allogenic organ transplantation.
9. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], systemic lupus
erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The
following are exceptions to this criterion:
i. Patients with vitiligo or alopecia ii. Patients with hypothyroidism (e.g.,
following Hashimoto syndrome) stable on hormone replacement iii. Any chronic skin
condition that does not require systemic therapy iv. Patients without active disease
in the last 5 years may be included
10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric
illness/social situations that would limit compliance with study requirement,
substantially increase risk of incurring AEs or compromise the ability of the patient
to give written informed consent.
11. Patients with prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial.
12. Previously untreated central nervous system (CNS) metastases or leptomeningeal
disease. Patients who have had whole brain radiation therapy (WBRT) during the
previous 2 weeks before treatment (no washout period is required for patients who have
received stereotactic body radiation therapy).
13. Active tuberculosis (clinical evaluation that includes clinical history, physical
examination and radiographic findings, and TB testing in line with local practice).
14. Current or prior use of immunosuppressive medication within 7 days before the first
dose of durvalumab. The following are exceptions to this criterion:
i. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection) ii. Systemic corticosteroids at doses not to exceed 20 mg/day of
prednisone or its equivalent iii. Steroids as premedication for hypersensitivity
reactions (e.g., CT scan premedication) iv. Decreasing dose of systemic
corticosteroids after radiation therapy for brain metastasis.
15. Receipt of live attenuated vaccine within 30 days prior to the first dose of
investigational product (IP). Note: Patients, if enrolled, should not receive live
vaccine whilst receiving study treatment and up to 30 days after the last dose of IP.
16. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control.
17. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
18. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 within 12 months
of the first dose of durvalumab.
19. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
