The purpose of this study is to test whether or not number of circulating cancer cells
detected in the blood can be decreased the by combining the standard treatment (durvalumab)
with additional chemotherapy
Primary objective is to measure the change in the levels of circulating tumor DNA (ctDNA) in
Cohort 1 (MRD+) due to the addition of platinum doublet chemotherapy in subjects with stage
III unresectable disease with positive DNA treated with consolidation chemotherapy and
immunotherapy.
Secondary Objectives:
- To determine the proportion of subjects in Cohort 1 MRD+ for whom ctDNA becomes
undetectable after chemotherapy
- To describe overall survival (OS) of subjects with baseline detectable ctDNA (Cohort 1
MRD+) vs baseline undetectable ctDNA (Cohort 2 MRD ) ·To describe progression free
survival (PFS) between subjects with baseline detectable (Cohort 1 MRD+) vs baseline
undetectable ctDNA (Cohort 2 MRD ) ·To describe the frequency and severity of toxicity
of consolidation durvalumab plus chemotherapy
Inclusion Criteria:
1. Histologically or cytologically documented NSCLC who present with locally advanced,
unresectable (stage III) disease (Version 8 of American Joint Committee on Cancer
(AJCC) Staging Manual)
2. Must have received at least 2 doses of platinum based chemotherapy concurrent with ≥
60 Gy definitive radiation therapy to all known tumor sites, and not have known
progression of disease.
3. Must have received, or be scheduled to receive, 2 prior doses of durvalumab
4. Willing to potentially receive further consolidation chemotherapy with carboplatin and
pemetrexed or carboplatin and paclitaxel as specified by the protocol, but not be
currently intended to receive additional consolidation chemotherapy apart from this
protocol
5. Aged 18 years or older
6. Weight > 30kg
7. Life expectancy ≥ 12 weeks
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
9. Absolute neutrophil count > 1.0 x 109/L (1000/mm3)
10. Platelets > 75 x 109/L (100,000/mm3)
11. Hemoglobin ≥ 9.0 g/dL (5.59 mmol/L)
12. Measured creatinine clearance > 40 mL/min, by either 24 hour urine collection or the
Cockcroft Gault formula
Males:
Mass(kg) x (140-Age) / 72 x serum creatinine (mg/dL)
Females:
Mass(kg) x (140-Age) x 0.85 / 72 x serum creatinine (mg/dL)
13. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN). This will not apply to subjects
with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is
predominantly unconjugated in the absence of evidence of hemolysis or hepatic
pathology) who will be allowed in consultation with their physician.
14. aspartate aminotransferase (AST) (SGOT)/Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5 x
institutional upper limit of normal (ULN) unless liver metastases are present, in
which case it must be ≤ 5 x ULN
15. Ability to understand and the willingness to sign the written IRB approved informed
consent document.
Exclusion Criteria:
1. Involvement in the planning and/or conduct of the study
2. Previous enrollment or randomization in the present study
3. Participation in another clinical study with an investigational product (ie, non
standard of care) during the last 4 weeks
4. Mixed small cell and non small cell lung cancer histology
5. Receiving or will receive sequential chemoradiation therapy for locally advanced NSCLC
6. History of another primary malignancy and currently undergoing active treatment (ie,
chemotherapy, hormonal therapy, biologics)
7. Current or prior use of immunosuppressive medication within 14 days before enrollment,
with the exceptions of intranasal and inhaled corticosteroids or systemic
corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. Systemic steroid administration required
to manage toxicities arising from radiation therapy delivered as part of the
chemoradiation therapy for locally advanced NSCLC is allowed.
8. Any unresolved toxicity CTCAE > Grade 2 from the prior chemoradiation therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria.
- Subjects with Grade ≥ 2 neuropathy will be evaluated on a case by case basis
after consultation with the Protocol Director / Principal Investigator
- Subjects with irreversible toxicity that is not reasonably expected to be
exacerbated by treatment with durvalumab may be included (ie, hearing loss) only
after consultation with the Protocol Director / Principal Investigator.
9. Any prior Grade ≥ 3 immune related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE > Grade 1) that may limit subject from
continuing durvalumab during the study
10. Recent major surgery within 4 weeks prior to entry into the study (excluding the
placement of vascular access) that would prevent administration of study drug.
11. Active or prior documented autoimmune or inflammatory disorders which could limit the
subjects ability to continue durvalumab on the study (including inflammatory bowel
disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of
diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener
syndrome [granulomatosis with polyangiitis; Graves' disease; rheumatoid arthritis;
hypophysitis; uveitis; etc]). The following may be taken in to considerations as
exceptions to this criterion:
1. Vitiligo or alopecia
2. Hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
3. Chronic skin condition not requiring systemic therapy
4. Those without active disease in the last 5 years may be included, but only after
consultation with the study physician
5. Celiac disease controlled by diet alone
12. History of primary immunodeficiency
13. History of organ transplant requiring therapeutic immunosuppression
14. History of hypersensitivity to durvalumab, carboplatin, pemetrexed or paclitaxel
15. Active infection including but not limited to:
- Tuberculosis
- Hepatitis B (HBV) [known positive results for HBV surface antigen (HBsAg) within
2 months prior to enrollment]. EXCEPTION: Subjects with a past or resolved HBV
infection, defined as the presence of hepatitis B core antibody (anti HBc) and
absence of HBsAg are eligible.
- Hepatitis C (HCV). EXCEPTION: Subjects positive for HCV antibody are eligible
only if polymerase chain reaction is negative for HCV RNA 16 .Receipt of live
attenuated vaccine within 30 days prior to the first dose of IP. Note: Subjects,
if enrolled, should not receive live vaccine while receiving the investigational
product (IP), and through 30 days after the last dose of IP.
17. 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
- Serious chronic gastrointestinal conditions associated with diarrhea
- Psychiatric illness/social situations that would limit compliance with study
requirement, substantially increase risk of incurring AEs or compromise the ability of
the subject to give written informed consent.
18. Female subjects who are pregnant or breast feeding; or subjects of reproductive
potential of any gender who are not employing or who do not agree to employ an
effective method of birth control prior to trial enrollment.
