Non-small Cell Lung Cancer (NSCLC)
Conditions
Brief summary
Based on promising data from our laboratory demonstrating synergy between ablative local radiotherapy and FLT3 ligand immunotherapy in murine NSCLC models, investigators are performing a phase II study combining FLT3L immunotherapy and SBRT for patients with advanced NSCLC that has progressed following standard systemic therapy. All patients will receive daily subcutaneous injections of CDX-301 (75 µg/kg) for 5 days, beginning on the first day of SBRT. SBRT will be delivered to a single pulmonary or extrapulmonary lesion. The SBRT regimen will depend on the size and location of the target lesion. The primary endpoint will be progression-free survival at 4 months, defined using immune-related response criteria (irRC).
Detailed description
Primary Objective * To explore the efficacy of combining stereotactic body radiotherapy (SBRT) with FLT3 ligand immunotherapy for advanced non-small cell lung cancer (NSCLC). Secondary Objectives * To establish the feasibility and safety of combining SBRT with FLT3 ligand immunotherapy for advanced NSCLC. * To quantify and evaluate potential surrogate outcomes for clinical efficacy of this treatment approach, including radiographic responses, immunologic responses, and circulating tumor cell levels.
Interventions
DRUGFLT3 Ligand Therapy (CDX-301)
See Arm 1 descriptions
RADIATIONStereotactic Body Radiotherapy (SBRT)
See Arm 1 descriptions
Sponsors
Montefiore Medical Center
Celldex Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* AJCC stage 3 or 4 histologically proven NSCLC not amenable to curative therapy * Age \>= 18 years * Prior treatment with at least one standard chemotherapy regimen or targeted agent prior to enrollment * Radiological assessment within 21 days prior to study entry demonstrating measurable disease that includes at least one pulmonary lesion . 1 cm in greatest dimension that would be amenable to SBRT and at least one measurable lesion that would be outside of the SBRT treatment fields * History/physical examination within 30 days prior to registration * ECOG performance status 0-2 * Signed, written informed consent
Exclusion criteria
* Less than 21 days between registration and the last receipt of chemotherapy, biotherapy, immunotherapy, radiotherapy (excluding palliative radiotherapy), or major surgery. Prior receipt of immunomodulatory therapy (eg: nivolumab) is permitted, as long as there has been a 21 day washout period following the most recent treatment. * Untreated central nervous system metastases. Patients with a history of brain metastases must have had no CNS-directed therapy within the past 60 days and radiological assessment within 30 days of study entry demonstrating a lack of progressive CNS disease * Ongoing or recent (within 21 days prior to study entry) use of high dose oral corticosteroids (.2 mg of dexamethasone daily or equivalent). Intranasal and/or inhaled corticosteroid use is permitted. * Any unresolved CTCAE grade \>2 toxicity from previous anti-cancer therapy. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study therapy (eg, hearing loss)may be enrolled after discussion with the principal investigators. * History of allogeneic organ transplant or autoimmune disease * Active malignancy, other than NSCLC, for which systemic therapy is indicated. History of adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy asides from hormonal therapy, adequately treated stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for \>= 5 years is permitted. * Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements as judged by the treating physicians * The following laboratory results, within 10 days of first study drug administration: * Hemoglobin . 9.0 g/dL, Absolute neutrophil count . 1.5 x 109/L, Platelet count . 100 x 109/L * Serum creatinine . 1.5 x ULN and creatinine clearance (by Cockcroft-Gault formula) \< 60 mL/min * Women of child bearing potential: positive pregnancy test (serum)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | 4 Months | The primary endpoint is progression-free survival rate at four months (PFS4), defined as the rate estimate of the percentage of patients who are alive and progression-free at 16 weeks (\~4 months) after initiation of study therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities (DLTs) | 30 days | The number of participants with evidence of DLTs will be tabulated. For the purposes of this study, a DLT will be defined as any grade 3-5 treatment-emergent adverse event toxicity, scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and occurring within 30 days after treatment with SBRT in combination with FLT3 ligand therapy (after the first treatment cycle). Asymptomatic laboratory abnormalities (eg: leukocytosis) that do not require intervention will not be counted as DLTs. For subjects who receive more than one "cycle" of SBRT and FLT3 ligand, only adverse events that occur after the first cycle will be scored as potential DLTs. |
| Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Up to 27 months post-randomization | Radiographic Response will be scored using RECIST V1.1 criteria based on 1st post-treatment imaging to quantify objective measures of change in tumor burden. RECIST uses a max of 10 target lesions per patient to determine when tumors in cancer patients improve, stay the same, or worsen during treatment. RECIST will be used to quantify the percentage of patients demonstrating Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), as follows: CR - resolution of all target lesions to background levels PR - at least 30% decrease in sum of diameters of target lesions (noting baseline diameters) SD - neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD (noting smallest sum on study) PD - at least 20% increase in sum of diameters of target lesions (noting smallest sum on study); absolute increase of 5mm must be demonstrated; \>=1 new lesion is considered PD If no CT/PET at a specific timepoint = "Not Evaluable" |
| Radiographic Response Rate Based on PET Response Criteria in Solid Tumors (PERCIST) | Up to 27 months post-randomization | Radiographic Response will be scored using PERCIST criteria based on the first PET imaging done. PERCIST is a set of rules that define when tumors in cancer patients improve, stay the same, or worsen during treatment, based on imaging data. PERCIST criteria will be used to quantify the percentage of patients demonstrating Complete Metabolic Response (CMR), Partial Metabolic Response (PMR), Stable Metabolic Disease (SMD), Progressive Metabolic Disease (PMD), or Not Evaluable (NE) as follows: CMR - complete resolution of 18F-FDG uptake, disappearance of all target lesions to background levels, no new 18F-FDG lesions PMR - reduction of a minimum of 30% in target measurable tumor 18F-FDG SUL peak, no increase \>30% in all lesions; no new lesions SMD - no CMR, PMR or PMD; no new lesions PMD - \>30% increase in 18F-FDG peak; OR visible increase in extent of tumor uptake; OR new 18F-FDG lesions If CT/PET was not done at a specific timepoint, result will be considered "Not Evaluable" |
| Overall Survival (OS) | From date of treatment to date of death, up to 5 years | Overall survival (OS) is defined as the percentage of patients alive at 5 years post-randomization. Data of subjects without a death record will be censored on the last known survival date. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNitin Ohri, MD
Albert Einstein College of Medicine
Participant flow
Recruitment details
The recruitment period spanned from July 2016 through 1/23/2020. All patients enrolled into the study were enrolled at Montefiore Medical Center.
Pre-assignment details
33 patients signed informed consent however 29 patients were enrolled and randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| SBRT + FLT3 Ligand Immunotherapy Patients will be treated with stereotactic body radiotherapy (SBRT) to a single pulmonary or extrapulmonary lesion as well as FLT3 immunotherapy.
FLT3 Ligand Therapy (CDX-301)
* Daily subcutaneous injections of CDX-301 (75 ug/kg) will be administered for 5 days, beginning on the first day of SBRT.
* Additional cycles of SBRT (to distinct lesions) and CDX-301 may be administered every 2-4 months to subjects who demonstrate evidence of clinical benefit (lack of treatment-related toxicity and no disease progression).
* Study therapy will be discontinued in cases of treatment-related toxicity or disease progression.
FLT3 Ligand Therapy (CDX-301): See Arm 1 descriptions
Stereotactic Body Radiotherapy (SBRT): See Arm 1 descriptions | 29 |
| Total | 29 |
Baseline characteristics
| Characteristic | SBRT + FLT3 Ligand Immunotherapy |
|---|---|
| Age, Customized <= 50 years | 3 Participants |
| Age, Customized 51-60 | 3 Participants |
| Age, Customized 61-70 | 9 Participants |
| Age, Customized 71-80 | 12 Participants |
| Age, Customized >81 | 2 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black | 8 Participants |
| Race/Ethnicity, Customized Hispanic | 9 Participants |
| Race/Ethnicity, Customized White | 11 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 26 / 29 |
| other Total, other adverse events | 29 / 29 |
| serious Total, serious adverse events | 23 / 29 |
Outcome results
Primary
Progression-Free Survival
The primary endpoint is progression-free survival rate at four months (PFS4), defined as the rate estimate of the percentage of patients who are alive and progression-free at 16 weeks (\ 4 months) after initiation of study therapy.
Time frame: 4 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SBRT + FLT3 Ligand Immunotherapy | Progression-Free Survival | 14 Participants |
Secondary
Dose Limiting Toxicities (DLTs)
The number of participants with evidence of DLTs will be tabulated. For the purposes of this study, a DLT will be defined as any grade 3-5 treatment-emergent adverse event toxicity, scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and occurring within 30 days after treatment with SBRT in combination with FLT3 ligand therapy (after the first treatment cycle). Asymptomatic laboratory abnormalities (eg: leukocytosis) that do not require intervention will not be counted as DLTs. For subjects who receive more than one cycle of SBRT and FLT3 ligand, only adverse events that occur after the first cycle will be scored as potential DLTs.
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SBRT + FLT3 Ligand Immunotherapy | Dose Limiting Toxicities (DLTs) | 4 Participants |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the percentage of patients alive at 5 years post-randomization. Data of subjects without a death record will be censored on the last known survival date.
Time frame: From date of treatment to date of death, up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SBRT + FLT3 Ligand Immunotherapy | Overall Survival (OS) | 3 Participants |
Secondary
Radiographic Response Rate Based on PET Response Criteria in Solid Tumors (PERCIST)
Radiographic Response will be scored using PERCIST criteria based on the first PET imaging done. PERCIST is a set of rules that define when tumors in cancer patients improve, stay the same, or worsen during treatment, based on imaging data. PERCIST criteria will be used to quantify the percentage of patients demonstrating Complete Metabolic Response (CMR), Partial Metabolic Response (PMR), Stable Metabolic Disease (SMD), Progressive Metabolic Disease (PMD), or Not Evaluable (NE) as follows: CMR - complete resolution of 18F-FDG uptake, disappearance of all target lesions to background levels, no new 18F-FDG lesions PMR - reduction of a minimum of 30% in target measurable tumor 18F-FDG SUL peak, no increase \>30% in all lesions; no new lesions SMD - no CMR, PMR or PMD; no new lesions PMD - \>30% increase in 18F-FDG peak; OR visible increase in extent of tumor uptake; OR new 18F-FDG lesions If CT/PET was not done at a specific timepoint, result will be considered Not Evaluable
Time frame: Up to 27 months post-randomization
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on PET Response Criteria in Solid Tumors (PERCIST) | Complete Metabolic Response (CMR) | 0 Participants |
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on PET Response Criteria in Solid Tumors (PERCIST) | Partial Metabolic Response (PMR) | 9 Participants |
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on PET Response Criteria in Solid Tumors (PERCIST) | Stable Metabolic Disease (SMD) | 9 Participants |
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on PET Response Criteria in Solid Tumors (PERCIST) | Progressive Metabolic Disease (PMD) | 11 Participants |
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on PET Response Criteria in Solid Tumors (PERCIST) | Not Evaluable | 0 Participants |
Secondary
Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST)
Radiographic Response will be scored using RECIST V1.1 criteria based on 1st post-treatment imaging to quantify objective measures of change in tumor burden. RECIST uses a max of 10 target lesions per patient to determine when tumors in cancer patients improve, stay the same, or worsen during treatment. RECIST will be used to quantify the percentage of patients demonstrating Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), as follows: CR - resolution of all target lesions to background levels PR - at least 30% decrease in sum of diameters of target lesions (noting baseline diameters) SD - neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD (noting smallest sum on study) PD - at least 20% increase in sum of diameters of target lesions (noting smallest sum on study); absolute increase of 5mm must be demonstrated; \>=1 new lesion is considered PD If no CT/PET at a specific timepoint = Not Evaluable
Time frame: Up to 27 months post-randomization
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response (CR) | 0 Participants |
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response (PR) | 4 Participants |
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Stable Disease (SD) | 8 Participants |
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Progressive Disease (PD) | 17 Participants |
| SBRT + FLT3 Ligand Immunotherapy | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Not Evaluable (NE) | 0 Participants |