Description:
Nivolumab is now the standard of care for second-line treatment of advanced squamous or
nonsquamous NSCLC regardless of the tumor's expression of PD-1L. CheckMate057 trial results
showed that in unselected patients with advanced or recurrent nonsquamous NSCLC who had
stopped responding to a platinum-based chemotherapy regimen, treatment with nivolumab
produced significantly better overall survival during follow-up as long as 18 months,
compared with a docetaxel-based regimen. But during the first 3 months on randomized
treatment, 15 more patients died in the nivolumab arm than in the docetaxel arm. This quickly
reversed during months 4-6 on treatment, when nine more patients died on docetaxel than on
nivolumab. A post hoc analysis showed a trend to a higher risk for death during the first 3
months of nivolumab treatment among patients with poorer prognostic features, more aggressive
disease, and low or no tumor expression of PD-L1. In addition, only a subgroup of patients
benefits from nivolumab with response rates of 20% in unselected cohorts and 10% in low PD-L1
expression cohort. Strategies to render the tumor micro-environment (TME) more susceptible to
anti-PD1 might include stimulation of anti-cancer immune responses by induction treatment
with low dose chemotherapy.
Given the potent immune-modulating effects and anti-tumor activity of cyclophosphamide and
doxorubicin, Investigator propose a study of combining nivolumab with induction therapy with
cyclophosphamide and doxorubicin for nonsquamous NSCLC with PD-L1 expression less than 10%.
Title
- Brief Title: Nivolumab After Cyclophosphamide and Doxorubicin Induction Therapy in NSCLC With PD-L1<10%
- Official Title: Nivolumab After Cyclophosphamide and Doxorubicin(CA) Induction Therapy in Previously Treated Advanced Non-squamous Cell Non-small Cell Lung Cancer With PD-L1<10%
Clinical Trial IDs
- ORG STUDY ID:
NCC2018-0267
- NCT ID:
NCT03808480
Conditions
- Non-small Cell Lung Cancer
Interventions
| Drug | Synonyms | Arms |
|---|
| CA and Nivolumab | Opdivo | CA and Nivolumab |
Purpose
Nivolumab is now the standard of care for second-line treatment of advanced squamous or
nonsquamous NSCLC regardless of the tumor's expression of PD-1L. CheckMate057 trial results
showed that in unselected patients with advanced or recurrent nonsquamous NSCLC who had
stopped responding to a platinum-based chemotherapy regimen, treatment with nivolumab
produced significantly better overall survival during follow-up as long as 18 months,
compared with a docetaxel-based regimen. But during the first 3 months on randomized
treatment, 15 more patients died in the nivolumab arm than in the docetaxel arm. This quickly
reversed during months 4-6 on treatment, when nine more patients died on docetaxel than on
nivolumab. A post hoc analysis showed a trend to a higher risk for death during the first 3
months of nivolumab treatment among patients with poorer prognostic features, more aggressive
disease, and low or no tumor expression of PD-L1. In addition, only a subgroup of patients
benefits from nivolumab with response rates of 20% in unselected cohorts and 10% in low PD-L1
expression cohort. Strategies to render the tumor micro-environment (TME) more susceptible to
anti-PD1 might include stimulation of anti-cancer immune responses by induction treatment
with low dose chemotherapy.
Given the potent immune-modulating effects and anti-tumor activity of cyclophosphamide and
doxorubicin, Investigator propose a study of combining nivolumab with induction therapy with
cyclophosphamide and doxorubicin for nonsquamous NSCLC with PD-L1 expression less than 10%.
Detailed Description
Nivolumab is now the standard of care for second-line treatment of advanced squamous or
nonsquamous non-small cell lung cancer (NSCLC) regardless of the tumor's expression of
programmed death-1 ligand (PD-1L). The 2015 Food and Drug Administration approval cited
results from the Open-Label Randomized Phase III Trial of Nivolumab Versus Docetaxel in
Previously Treated Metastatic nonsquamous-NSCLC (CheckMate057) trial. Those results showed
that in unselected patients with advanced or recurrent nonsquamous NSCLC who had stopped
responding to a platinum-based chemotherapy regimen, treatment with nivolumab produced
significantly better overall survival during follow-up as long as 18 months, compared with a
docetaxel-based regimen. But a more detailed assessment of the survival data showed an
unexpected pattern of an early hazard among the nivolumab patients. During the first 3 months
on randomized treatment, 15 more patients died in the nivolumab arm than in the docetaxel
arm. This quickly reversed during months 4-6 on treatment, when nine more patients died on
docetaxel than on nivolumab. By 12 months after the onset of treatment, overall survival was
51% in the nivolumab group and 39% among those randomized to docetaxel. A post hoc analysis
showed a trend to a higher risk for death during the first 3 months of nivolumab treatment
among patients with poorer prognostic features, more aggressive disease, and low or no tumor
expression of PD-L1. In addition, only a subgroup of patients benefits from nivolumab with
response rates of 20% in unselected cohorts and 10% in low PD-L1 expression cohort.
Strategies to render the tumor micro-environment (TME) more susceptible to anti-PD1 might
include stimulation of anti-cancer immune responses by induction treatment with low dose
chemotherapy.
Cyclophosphamide, an old-school chemotherapeutic agent used across a wide range of
malignancies, was found to be a potent immune modulator that targets suppressive regulatory
immune cells within the tumor microenvironment while enhancing effector cells. However,
cyclophosphamide has a limited effect on TIL from tumors larger than a few mm diameter in
view of an increased percentage of myeloid derived suppressor cells (MDSC). Meanwhile,
doxorubicin is also has a potent immune-modulating activity, which can selectively impair
MDSC-induced immunosuppression. Additionally, both cyclophosphamide and doxorubicin have
anti-tumor activity against NSCLC. Given the potent immune-modulating effects and anti-tumor
activity of cyclophosphamide and doxorubicin, Investigator propose a study of combining
nivolumab with induction therapy with cyclophosphamide and doxorubicin for nonsquamous NSCLC
with PD-L1 expression less than 10%.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| CA and Nivolumab | Experimental | After 1 cycle of cyclophosphamide and doxorubicin (CA) induction therapy, Nivolumab 360mg flat dose will be given on day 1 with CA chemotherapy in a 21-day cycle.
After the completion of 4 cycles of CA chemotherapy, Nivolumab will be continued as a single agent at a dose of 480mg flat dose every 4 weeks until loss of clinical benefit | |
Eligibility Criteria
Inclusion Criteria:
- Histologic or cytologic diagnosis of nonsquamous NSCLC with SP263 PD-L1 expression
<10%
- Patients whose tumor is not known to have anaplastic lymphoma kinase(ALK) or epidermal
growth factor receptor(EGFR) mutation and Previously treated with at least one
platinum-based chemotherapy but less than 3 prior chemotherapy
- Before study entry, a minimum of 21 days must have elapsed since any prior
chemotherapy.
- Prior radiation therapy is allowed as long as the irradiated area is not the only
source of measurable disease.
- No other forms of cancer therapy, such as immunotherapy for at least 2 weeks before
the enrollment in study.
- Performance status of 0-1 on the ECOG criteria.
- At least one unidimensionally measurable lesion meeting Response Evaluation Criteria
in Solid Tumors (Revised RECIST guideline version 1.1)
- Estimated life expectancy of at least 8 weeks.
- Patient compliance that allow adequate follow-up. Adequate hematologic (WBC ≥4,000/mm3
또는 4.0 x 103/㎕ Platelet count ≥130,000mm3 또는 130 x 103/㎕ Bilirubin total ≤1.0 mg/dL
AST/ALT≤ 80 IU/L creatinine concentration 1XULN or creatinine clearance (CrCl) > 50
mL/min (measured using the Cockcroft-Gault formula)
- Informed consent from patient or patient's relative.
- Males or females at least 18 years of age.
Exclusion Criteria:
- Previous therapy with anti-PD-1 or -PD-L1 inhibitors
- Persistence of clinically relevant therapy related toxicities from previous
chemotherapy and/or radiotherapy
- Has received prior chemotherapy or tyrosine kinase inhibitor therapy within 3 weeks of
the first dose of trial treatment ; completed palliative radiotherapy(except for brain
and extremities) within 2weeks of the first dose of trial treatment. Prior curative
thoracic radiation therapy(>=60Gy) is permitted if disease progression occured >4weeks
after the completion of therapy.
- Treatment with other investigational drugs or treatment in another clinical trial
within the past three weeks before start of therapy or concomitantly with this trial
- Has received a live vaccine(Concomitant yellow fever vaccin) within 4 weeks prior to
the first administration of study medication. Concomitant yellow fever vaccination
- Active CNS metastases
- Spinal cord compression not definitively treated with surgery and/or radiation or
previously diagnosed and treated spinal cord compression without evidence that disease
has been clinically stable for 2 weeks prior to randomization
- Leptomeningeal disease
- Significant cardiovascular diseases (i.e., hypertension not controlled by medical
therapy, unstable angina, history of myocardial infarction within the past 12 months,
congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion)
- Proteinuria CTCAE grade 2 or greater
- Significant weight loss (> 10 %) within the past 6 weeks prior to treatment in the
present trial
- Current peripheral neuropathy ≥ CTCAE(version4.0) Grade 2 except due to trauma
- Major injuries and/or surgery with incomplete wound healing within the past ten days
prior to enrollment
- Serious infections requiring systemic antibiotic (e.g. antiviral, antimicrobial,
antifungal) therapy
- Active hepatitis C and/or B infection
- Known human immunodeficiency virus (HIV) seropositivity
- Serious illness or concomitant non-oncological disease such as
neurologic-,psychiatric-, infectious disease or active ulcers (gastro-intestinal
tract, skin) or laboratory abnormality that may increase the risk associated with
study participation or study drug administration and in the judgment of the
investigator would make the patient inappropriate for entry into the study
- Patients who are sexually active and unwilling to use a medically acceptable method of
contraception (e.g. such as implants, injectables, combined oral contraceptives, some
intrauterine devices or vasectomized partner for participating females, condoms for
participating males) during the trial and for at least 7 months after end of active
therapy
- Pregnancy or breast feeding
- Psychological, familial, sociological or geographical factors potentially hampering
compliance with the study protocol and follow-up schedule
- Patients unable to comply with the protocol
- Active alcohol or drug abuse
- Other malignancy within the past three years other than basal cell skin cancer or
carcinoma in situ of the cervix
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | objective response |
| Time Frame: | From date of first administration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48months |
| Safety Issue: | |
| Description: | objective response rate using RECIST v1.1 |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | National Cancer Center, Korea |
Last Updated
September 10, 2020
