Metastatic Non Small Cell Lung Cancer
Conditions
Keywords
Metastatic, Lung Cancer, Switch, Maintenance, Pembrolizumab.
Brief summary
Single arm one stage Phase II study: post 4-6 cycles platinum doublet chemotherapy for patients with metastatic Non Small Cell Lung Cancer (NSCLC) offering Pembrolizumab as maintenance therapy to non-progressors with primary endpoint: Immune Related Progression Free Survival (irPFS) at 1 year. Aim to show that this is at least 25% (compared to an expected 12% 1 year PFS based on the Pemetrexed and Erlotinib maintenance trials).
Detailed description
Rationale: There are currently no data on maintenance therapy with PD1/ PDL1 inhibitors in NSCLC. After an initial response / stable disease to first line chemotherapy, non-progressors / candidates for maintenance treatment, represent an ideal setting / patient group to test the efficacy of Pembrolizumab given that chemotherapy results in antigen release, hence it has the potential to augment immune checkpoint blockade, and following disease cytoreduction, this represents a lower disease burden setting, that may suit checkpoint inhibition better given the recent studies in Prostate cancer with Ipilimumab and Melanoma with Pembrolizumab(suggesting better outcomes for patients with less extensive disease). Primary endpoint: percentage of patients that have not progressed at 1 year using immune related radiological criteria. All patients to be treated with fixed dose 200mg iv Pembrolizumab until unacceptable toxicity, disease progression or completion of 2 years therapy. Statistical Analysis Plan Summary The study employs a one stage phase II Fleming's design using irPFS at 1 year as primary endpoint. Using response hypotheses of H0 \< 12 % and Ha\> 25% i.e. that the irPFS at 1 year for the maintenance Pembrolizumab arm is 25%, compared to 12% in the normal chemotherapy maintenance arm, with a significance level (i.e., the probability of rejecting H0 when it is true) α=0.05 and the power (i.e. the probability of deciding the regimen is active) is 0.8 when true response rate is 25%, 48 patients are required to be entered into this study. Entry Criteria Diagnosis/Condition for Entry into the Trial In order to be eligible for trial entry, patients must have a diagnosis of metastatic Non Small Cell Lung Cancer, and should not have progressed after first line palliative chemotherapy with a platinum doublet. They should have received no more than six (6) cycles of a platinum doublet chemotherapy, and should be able to receive treatment within three (3) to six (6) weeks from the last chemotherapy administration.
Interventions
DRUGPembrolizumab
Switch maintenance pembrolizumab treatment
Sponsors
Merck Sharp & Dohme LLC
Bank of Cyprus Oncology Centre
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
* In order to be eligible for participation in this trial, the subject must: 1. Be willing and able to provide written informed consent/assent for the trial. 2. Be above 18 years of age on day of signing informed consent. 3. Have measurable disease based on RECIST 1.1. 4. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor. 5. Have a performance status of 0 to 2 on the ECOG Performance Scale. 6. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation. Table 1 Adequate Organ Function Laboratory Values System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) Renal Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN, AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases Albumin \>2.5 g/L Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. 7. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 8. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 9. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Exclusion criteria
The subject must be excluded from participating in the trial if the subject: 1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 2. Have completed more than six (6) cycles of first line platinum doublet chemotherapy or more than six (6) have elapsed from the last chemotherapy administration of the first line chemotherapy with platinum doublet. 3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 4. Has a known history of active TB (Bacillus Tuberculosis) 5. Hypersensitivity to pembrolizumab or any of its excipients. 6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. * Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 8. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 11. Has known history of, or any evidence of active, non-infectious pneumonitis. 12. Has an active infection requiring systemic therapy. 13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). 19. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immune Related Progression Free Survival (irPFS) at 1 Year | 4 years | To investigate whether treatment with pembrolizumab improves 1 year irPFS, compared to historical controls (from the Pemetrexed and Erlotinib maintenance trials). Aim to show that this is at least 25% (compared to an expected 12% 1 year PFS based on the Pemetrexed and Erlotinib maintenance trials) using a one stage phase II Fleming's design. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rates With Immune Related Response Criteria (irRC) | 7 years | Response rates according to RECIST criteria. Time from randomization of the first patient until database cut-off date for the final analysis (Jul 2016 - May 2023; approximately 7 years). |
| Radiological Progression Free Survival (PFS) Using RECIST Criteria Version 1.1 | 7 years | PFS calculated using RECIST criteria. RECIST Criteria Version 1.1: Complete response(CR): Disappearance of all target lesions. Partial response(PR): At least a 30% decrease in the sum of diameters of all target lesions, (from baseline sum of diameters in the absence of CR). Progressive disease(PD): Any new lesion or at least a 20% increase in the sum of diameters of target lesions, (from the smallest sum of diameters at prior timepoints -including baseline). Stable disease(SD): Neither CR or a PR nor sufficient increase to qualify for PD. Immune related irPFS calculated using Immune related Response criteria where upon PD there a CT scan would be repeated in 4-6 weeks to exclude pseudoprogression.. |
| Response Rates Using RECIST Version 1.1 | 7 years | Response rates according to RECIST criteria Version 1.1 where Complete response(CR): Disappearance of all target lesions. Partial response(PR): At least a 30% decrease in the sum of diameters of all target lesions, (from baseline sum of diameters in the absence of CR). Progressive disease(PD): Any new lesion or at least a 20% increase in the sum of diameters of target lesions, (from the smallest sum of diameters at prior timepoints -including baseline). Stable disease(SD): Neither CR or a PR nor sufficient increase to qualify for PD. |
| Overall Survival | 7 years | Defined as time from the date of randomisation until death from any cause or time to the last follow up appointment (censored). |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 7 years | Assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment. |
| Immune-related PFS Using irRC | 7 years | PFS calculated using RECIST criteria. Immune related irPFS calculated using Immune related Response criteria. |
Countries
Cyprus
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Study experimental treatment with maintenance pembrolizumab
Pembrolizumab: Switch maintenance pembrolizumab treatment | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Clinical Deterioration | 3 |
| Overall Study | Death | 2 |
| Overall Study | Disease Progression | 34 |
Baseline characteristics
| Characteristic | Single Arm Study |
|---|---|
| Age, Continuous | 66 years |
| Age, Customized <70 years | 30 Participants |
| Age, Customized ≥70 years | 18 Participants |
| Number of Participants | 48 participant |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 47 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 42 / 48 |
| other Total, other adverse events | 48 / 48 |
| serious Total, serious adverse events | 13 / 48 |
Outcome results
Primary
Immune Related Progression Free Survival (irPFS) at 1 Year
To investigate whether treatment with pembrolizumab improves 1 year irPFS, compared to historical controls (from the Pemetrexed and Erlotinib maintenance trials). Aim to show that this is at least 25% (compared to an expected 12% 1 year PFS based on the Pemetrexed and Erlotinib maintenance trials) using a one stage phase II Fleming's design.
Time frame: 4 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm Study | Immune Related Progression Free Survival (irPFS) at 1 Year | 16 Participants |
Secondary
Immune-related PFS Using irRC
PFS calculated using RECIST criteria. Immune related irPFS calculated using Immune related Response criteria.
Time frame: 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm Study | Immune-related PFS Using irRC | 6.3 months |
Secondary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
Assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment.
Time frame: 7 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm Study | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Experienced treatment related adverse event (any grade) | 42 Participants |
| Single Arm Study | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Experienced any adverse event (any grade) | 48 Participants |
| Single Arm Study | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | Experienced treatment related adverse event of grade 3-5 | 11 Participants |
Secondary
Overall Survival
Defined as time from the date of randomisation until death from any cause or time to the last follow up appointment (censored).
Time frame: 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm Study | Overall Survival | 12.2 months |
Secondary
Radiological Progression Free Survival (PFS) Using RECIST Criteria Version 1.1
PFS calculated using RECIST criteria. RECIST Criteria Version 1.1: Complete response(CR): Disappearance of all target lesions. Partial response(PR): At least a 30% decrease in the sum of diameters of all target lesions, (from baseline sum of diameters in the absence of CR). Progressive disease(PD): Any new lesion or at least a 20% increase in the sum of diameters of target lesions, (from the smallest sum of diameters at prior timepoints -including baseline). Stable disease(SD): Neither CR or a PR nor sufficient increase to qualify for PD. Immune related irPFS calculated using Immune related Response criteria where upon PD there a CT scan would be repeated in 4-6 weeks to exclude pseudoprogression..
Time frame: 7 years
Population: In order to be eligible for trial entry, patients must have a diagnosis of metastatic Non Small Cell Lung Cancer, and should not have progressed after first line palliative chemotherapy with a platinum doublet. They should have received no more than six (6) cycles of a platinum doublet chemotherapy, and should be able to receive treatment within three (3) to six (6) weeks from the last chemotherapy administration.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm Study | Radiological Progression Free Survival (PFS) Using RECIST Criteria Version 1.1 | 2.1 months |
Secondary
Response Rates Using RECIST Version 1.1
Response rates according to RECIST criteria Version 1.1 where Complete response(CR): Disappearance of all target lesions. Partial response(PR): At least a 30% decrease in the sum of diameters of all target lesions, (from baseline sum of diameters in the absence of CR). Progressive disease(PD): Any new lesion or at least a 20% increase in the sum of diameters of target lesions, (from the smallest sum of diameters at prior timepoints -including baseline). Stable disease(SD): Neither CR or a PR nor sufficient increase to qualify for PD.
Time frame: 7 years
Population: In order to be eligible for trial entry, patients must have a diagnosis of metastatic Non Small Cell Lung Cancer, and should not have progressed after first line palliative chemotherapy with a platinum doublet. They should have received no more than six (6) cycles of a platinum doublet chemotherapy, and should be able to receive treatment within three (3) to six (6) weeks from the last chemotherapy administration.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm Study | Response Rates Using RECIST Version 1.1 | Partial Response | 6 Participants |
| Single Arm Study | Response Rates Using RECIST Version 1.1 | Non- Responders | 41 Participants |
| Single Arm Study | Response Rates Using RECIST Version 1.1 | Complete Response | 1 Participants |
Secondary
Response Rates With Immune Related Response Criteria (irRC)
Response rates according to RECIST criteria. Time from randomization of the first patient until database cut-off date for the final analysis (Jul 2016 - May 2023; approximately 7 years).
Time frame: 7 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm Study | Response Rates With Immune Related Response Criteria (irRC) | Complete Response | 1 Participants |
| Single Arm Study | Response Rates With Immune Related Response Criteria (irRC) | Partial Response | 6 Participants |
| Single Arm Study | Response Rates With Immune Related Response Criteria (irRC) | Non Responders | 41 Participants |