Non Small Cell Lung Cancer
Conditions
Keywords
lung, cancer, gp96, vaccine, immunotherapy, Heat Biologics, cyclophosphamide, vinorelbine, erlotinib, gemcitabine, paclitaxel, docetaxel, pemetrexed
Brief summary
Determine whether viagenpumatucel-L combined with low-dose cyclophosphamide prolongs survival in patients with NSCLC who failed 2 or 3 prior lines of therapy for incurable or metastatic disease compared with chemotherapy alone.
Detailed description
This study will test whether vaccination with viagenpumatucel-L combined with low-dose cyclophosphamide will prolong the survival of patients with non-small cell lung cancer (NSCLC) who have failed 2 or 3 prior lines of therapy for incurable or metastatic disease compared with chemotherapy alone. Patients will be randomized 2 to 1 into the viagenpumatucel-L arm and the chemotherapy alone arm, respectively.
Interventions
Vaccine derived from irradiated human lung cancer cells genetically engineered to continually secrete gp96-Ig
One 50mg tablet administered orally daily for 7 days on alternating weeks for a total of 6 weeks of therapy over 12 weeks
DRUGPhysician's Choice Regimen (Vinorelbine, Erlotinib, Gemcitabine, Paclitaxel, Docetaxel, Pemetrexed)
Physician will select one of the following to be given in nominal 21 day cycles with dose and route according to investigator's standard practice: * Vinorelbine * Erlotinib * Gemcitabine * Paclitaxel * Docetaxel * Pemetrexed
Sponsors
Heat Biologics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Non-small cell lung adenocarcinoma * At least 2 and no more than 3 prior lines of therapy for incurable or metastatic NSCLC * Suitable for conventional single agent chemotherapy * Disease progression at study entry * Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1; PS=2 patients may be considered * Central nervous system (CNS) metastases may be permitted but must be treated and neurologically stable * Adequate laboratory parameters * Willing and able to comply with the protocol and sign informed consent * Female patients who are of childbearing potential and fertile male patients must agree to use an effective form of contraception throughout study participation
Exclusion criteria
* Received systemic anticancer therapy or radiation therapy within the previous 14 days * Received more than 3 lines of prior conventional therapy for advanced disease * Human immunodeficiency virus (HIV), hepatitis B or C, or severe/uncontrolled infections or intercurrent illness, unrelated to the tumor, requiring active therapy * Any condition requiring concurrent systemic immunosuppressive therapy * Known immunodeficiency disorders * Known leptomeningeal disease * Other active malignancies * Prior treatment with a cancer vaccine for this indication * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 3 years | Overall survival (OS) calculated as the duration of survival from the date of randomization to the date of death from any cause, or was censored on the date the patient was last known to be alive. Survival time was calculated from the randomization date up to the date of death,or censored on the date that the patient was last known to be alive (last available visit date) utilizing Kaplan-Meier Estimate of Overall Survival Ending Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Up to 3 years | Evaluate overall immune-related DCR (irDCR) and also DCR by Response Evaluation Criteria in Solid Tumors (RECIST) (complete response, partial response, and stable disease) |
| 6-Month Disease Control Rate (6mDCR) | 6 months | Evaluate 6-month immune-related DCR (6m-irDCR) and also 6mDCR by RECIST (complete response, partial response, and stable disease at 6 months following randomization) |
| Overall Response Rate (ORR) | Up to 3 years | Evaluate immune-related ORR (irORR) and also ORR by RECIST (complete response and partial response) |
| Progression-Free Survival (PFS) | Up to 3 years | Evaluate immune-related PFS (irPFS) and PFS by RECIST (Response Evaluation Criteria for Solid Tumors) |
| Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Up to 3 years | Evaluate the safety of the combination of viagenpumatucel-L and low-dose cyclophosphamide by frequency of Treatment-Emergent Adverse Events |
| Survival at 6 Months | 6 months | Evaluate the proportion of patients who are alive at 6 months following randomization |
| Survival at 12 Months | 12 months | Evaluate the proportion of patients who are alive at 12 months following randomization |
| Immune Response | Up to 3 years | Characterize the peripheral blood immunologic response via intracellular cytokine staining (ICS) by flow cytometry and/or enzyme-linked immunosorbent spot (ELISPOT) on cluster of differentiation 8 positive (CD8+) cells following vaccination |
| Time to Progression (TTP) | Up to 3 years | Evaluate immune-related TTP (irTTP) and also TTP (Time to Progression) by RECIST |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide Viagenpumatucel-L (HS-110) given as 1\*10\^7 cells for 12 weekly injections followed by injections every 9 weeks for up to 12 months or until discontinuation from study treatment, whichever occurs first, plus metronomic cyclophosphamide therapy for the first 12 weeks.
Viagenpumatucel-L: Vaccine derived from irradiated human lung cancer cells genetically engineered to continually secrete gp96-Ig
Metronomic Cyclophosphamide: One 50mg tablet administered orally daily for 7 days on alternating weeks for a total of 6 weeks of therapy over 12 weeks | 45 |
| Chemotherapy Alone Patients will be treated with a physician's choice regimen until progression.
Physician's Choice Regimen (Vinorelbine, Erlotinib, Gemcitabine, Paclitaxel, Docetaxel, Pemetrexed): Physician will select one of the following to be given in nominal 21 day cycles with dose and route according to investigator's standard practice:
* Vinorelbine
* Erlotinib
* Gemcitabine
* Paclitaxel
* Docetaxel
* Pemetrexed | 21 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Death | 5 | 0 |
| Overall Study | Patient returned to primary oncologist | 0 | 1 |
| Overall Study | Patient took treatment break | 0 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Progressive Disease | 26 | 9 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Randomized in Error | 1 | 0 |
| Overall Study | Significant Clinical Progression | 7 | 4 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Chemotherapy Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 9 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 12 Participants | 33 Participants |
| Age, Continuous | 65.6 years STANDARD_DEVIATION 8.9 | 63.0 years STANDARD_DEVIATION 10.5 | 64.8 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 21 Participants | 65 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 44 Participants | 18 Participants | 62 Participants |
| Region of Enrollment Australia | 7 Participants | 3 Participants | 10 Participants |
| Region of Enrollment United States | 38 Participants | 18 Participants | 56 Participants |
| Sex: Female, Male Female | 27 Participants | 10 Participants | 37 Participants |
| Sex: Female, Male Male | 18 Participants | 11 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 43 | 0 / 20 |
| other Total, other adverse events | 19 / 43 | 9 / 20 |
| serious Total, serious adverse events | 17 / 43 | 8 / 20 |
Outcome results
Primary
Overall Survival (OS)
Overall survival (OS) calculated as the duration of survival from the date of randomization to the date of death from any cause, or was censored on the date the patient was last known to be alive. Survival time was calculated from the randomization date up to the date of death,or censored on the date that the patient was last known to be alive (last available visit date) utilizing Kaplan-Meier Estimate of Overall Survival Ending Events
Time frame: Up to 3 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Overall Survival (OS) | 176 Days |
| Chemotherapy Alone | Overall Survival (OS) | 372 Days |
p-value: 0.0011Log Rank
Comparison: With only 50% of enrollment complete prior to study termination by sponsor, insufficient sample size exists to fully complete efficacy analysis.p-value: <0.05Other
Secondary
6-Month Disease Control Rate (6mDCR)
Evaluate 6-month immune-related DCR (6m-irDCR) and also 6mDCR by RECIST (complete response, partial response, and stable disease at 6 months following randomization)
Time frame: 6 months
Population: Data were not collected for Outcome Measure 4 due to study termination (50% enrollment) by the Sponsor on 01 September 2015 due to changing treatment landscape (PD-1 approvals), and a subsequent change in development focus to Immuno-Oncology (IO) combinations. See NCT02439450.
Secondary
Disease Control Rate (DCR)
Evaluate overall immune-related DCR (irDCR) and also DCR by Response Evaluation Criteria in Solid Tumors (RECIST) (complete response, partial response, and stable disease)
Time frame: Up to 3 years
Population: Data were not collected for Outcome Measure 3 due to study termination (50% enrollment) by the Sponsor on 01 September 2015 due to changing treatment landscape (PD-1 approvals), and a subsequent change in development focus to Immuno-Oncology (IO) combinations. See NCT02439450.
Secondary
Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE)
Evaluate the safety of the combination of viagenpumatucel-L and low-dose cyclophosphamide by frequency of Treatment-Emergent Adverse Events
Time frame: Up to 3 years
Population: Safety was defined as the number of adverse events (AE)/serious adverse events (SAE) in patients receiving viagenpumatucel-L and low-dose Cyclophosphamide (CY).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one TEAE | 41 Participants |
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Fatal TEAE | 7 Participants |
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one treatment-related TEAE | 32 Participants |
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one TEAE Leading to Tx Discontinuation | 7 Participants |
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one severe TEAE | 25 Participants |
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one TEAE Leading to a Dose Reduction | 0 Participants |
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one SAE | 17 Participants |
| Chemotherapy Alone | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one TEAE Leading to a Dose Reduction | 2 Participants |
| Chemotherapy Alone | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one TEAE | 20 Participants |
| Chemotherapy Alone | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one severe TEAE | 11 Participants |
| Chemotherapy Alone | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one treatment-related TEAE | 15 Participants |
| Chemotherapy Alone | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one SAE | 8 Participants |
| Chemotherapy Alone | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | Fatal TEAE | 0 Participants |
| Chemotherapy Alone | Frequency of Adverse Events: Number of Participants With Treatment-Emergent Adverse Events (TEAE) | At least one TEAE Leading to Tx Discontinuation | 2 Participants |
Secondary
Immune Response
Characterize the peripheral blood immunologic response via intracellular cytokine staining (ICS) by flow cytometry and/or enzyme-linked immunosorbent spot (ELISPOT) on cluster of differentiation 8 positive (CD8+) cells following vaccination
Time frame: Up to 3 years
Population: Data were not collected for Outcome Measure 10 due to study termination (50% enrollment) by the Sponsor on 01 September 2015 due to changing treatment landscape (PD-1 approvals), and a subsequent change in development focus to Immuno-Oncology (IO) combinations. See NCT02439450.
Secondary
Overall Response Rate (ORR)
Evaluate immune-related ORR (irORR) and also ORR by RECIST (complete response and partial response)
Time frame: Up to 3 years
Population: Data were not collected for Outcome Measure 5 due to study termination (50% enrollment) by the Sponsor on 01 September 2015 due to changing treatment landscape (PD-1 approvals), and a subsequent change in development focus to Immuno-Oncology (IO) combinations. See NCT02439450.
Secondary
Progression-Free Survival (PFS)
Evaluate immune-related PFS (irPFS) and PFS by RECIST (Response Evaluation Criteria for Solid Tumors)
Time frame: Up to 3 years
Population: Calculated from randomization date to earliest date of first 'Progressive Disease' response (Immune-Related / RECIST Response Criteria) or date of death, and censored on the date of the last available post-baseline tumor assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Progression-Free Survival (PFS) | immune-related PFS (irPFS) | 76.0 Days |
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Progression-Free Survival (PFS) | Progression Free Survival (PFS) | 70.0 Days |
| Chemotherapy Alone | Progression-Free Survival (PFS) | immune-related PFS (irPFS) | 190.0 Days |
| Chemotherapy Alone | Progression-Free Survival (PFS) | Progression Free Survival (PFS) | 190.0 Days |
Secondary
Survival at 12 Months
Evaluate the proportion of patients who are alive at 12 months following randomization
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Survival at 12 Months | 8 Participants |
| Chemotherapy Alone | Survival at 12 Months | 11 Participants |
Secondary
Survival at 6 Months
Evaluate the proportion of patients who are alive at 6 months following randomization
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Survival at 6 Months | 21 Participants |
| Chemotherapy Alone | Survival at 6 Months | 17 Participants |
Secondary
Time to Progression (TTP)
Evaluate immune-related TTP (irTTP) and also TTP (Time to Progression) by RECIST
Time frame: Up to 3 years
Population: Time to immune-related progression was calculated from the randomization date up to the date of the first 'Progressive Disease' response (Immune-Related Response Criteria) Time to progression was calculated from the randomization date up to the date of the first 'Progressive Disease' response (RECIST Response Criteria).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Time to Progression (TTP) | immune-related TTP (irTTP) | 67.0 Days |
| Viagenpumatucel-L Plus Metronomic Cyclophosphamide | Time to Progression (TTP) | Time to Progression (TTP) | 67.5 Days |
| Chemotherapy Alone | Time to Progression (TTP) | immune-related TTP (irTTP) | 71.0 Days |
| Chemotherapy Alone | Time to Progression (TTP) | Time to Progression (TTP) | 73.5 Days |