Resectable, Early-stage, NSCLC
Conditions
Keywords
Neoadjuvant, Non-small Cell Lung Cancer, Cancer, Lung, Resectable, Early-stage, Stage I, Stage II, Stage IIIA, Durvalumab
Brief summary
Study D9108C00002 (NeoCOAST) is a platform study assessing the effectiveness and safety of neoadjuvant durvalumab alone or in combination with novel agents in participants with resectable, early-stage (Stage I \[\>2cm\] to IIIA) non-small cell lung cancer (NSCLC).
Interventions
DRUGDurvalumab
Durvalumab 1500 mg IV will be administered Q4W (on Week 1 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period.
COMBINATION_PRODUCTOleclumab
Oleclumab 3000 mg IV will be administered Q2W (on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period.
COMBINATION_PRODUCTMonalizumab
Monalizumab 750 mg IV will be administered Q2W (on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period.
COMBINATION_PRODUCTDanvatirsen
Danvatirsen 200 mg IV will be administered on Days 1, 3, and 5 of Week 0 (7-day danvatirsen lead-in period) and later every week (on Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, and Week 4 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period.
Sponsors
MedImmune LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants will be enrolled and randomized into a durvalumab monotherapy arm or into a durvalumab plus other novel therapy arms. Up to approximately 25 sites globally will participate in this study. New treatment arms may be added in the future. Participants will be treated with a single durvalumab dose alone or in combination with other agents. After the single cycle treatment period participants will have the standard surgical resection planned. All participants will have a post-resection monitoring visit. Study treatment will be discontinued upon disease progression, unacceptable toxicity, or other investigators' reasons.
Eligibility
Sex/Gender
ALL
Age
18 Years to 102 Years
Healthy volunteers
No
Inclusion criteria
1. Cytologically and/or histologically-documented NSCLC 1. Stage I (\> 2 cm) to IIIA (for participants with N2 disease, only those with 1 single nodal station ≤ 3 cm are eligible) NSCLC according to the 8th edition of American Joint Committee on Cancer staging classification 2. Amenable to complete surgical resection 3. Have not received any other therapy for this condition 2. Predicted forced expiratory volume in one second (FEV1) ≥ 50% 3. Predicted diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 50% 4. ECOG 0 or 1 5. Adequate organ function
Exclusion criteria
1. Participants with small-cell lung cancer or mixed small-cell lung cancer 2. Participants who require or may require pneumonectomy 3. Prior treatment with programmed cell death ligand-1 (PD-L1), PD-L1, or cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors 4. Current or prior use of immunosuppressive medication within 14 days before the first dose of study drug. 5. Active or prior documented autoimmune or inflammatory disorders. The following are exceptions to this criterion: 1. Participants with vitiligo or alopecia 2. Participants with hypothyroidism on hormone replacement 3. Any chronic skin condition that does not require systemic therapy 4. Participants without active disease in the last 5 years may be included but only after consultation with the study physician 5. Participants with celiac disease controlled by diet alone 6. Pregnant or breast-feeding female 7. Major surgical procedure within prior 30 days 8. History of active primary immunodeficiency 9. Active infection including tuberculosis, hepatitis B, hepatitis C, or HIV 10. QTc interval (QTc) ≥ 470 ms 11. Uncontrolled intercurrent illness that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent 12. Receipt of live attenuated vaccination within 30 days prior to study entry 13. History of another primary malignancy except for: 1. Curative-treated malignancy with no known active disease \> 2 years before enrollment on the study 2. Curative-treated non-melanoma skin cancer and/or carcinoma in-situ
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response Rate | Day 1 through Day 42 | Major pathological response rate is defined as percentage of participants with \<=10% residual viable tumor cells in the resected specimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (pCR) Rate | Day 1 through Day 42 | The pCR rate is defined as percentage of participants with no residual viable tumor cells in the resected specimen. |
| Feasibility to Surgery | Day 29 to Day 42 after Week 1 Day 1 | Feasibility to surgery is defined as the percentage of participants who underwent the planned surgery within Days 29 to 42 after Week 1 Day 1. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | From Day 1 through Day 105 | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. |
| Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | From Day 1 through Day 105 | Participants with Grade 3 or Grade 4 clinical laboratory toxicities are reported. Laboratory tests included hematology, coagulation, chemistry, and urinalysis. |
| Number of Participants With Abnormal Vital Signs Reported as TEAEs | From Day 1 through Day 105 | Participants with abnormal vital sign reported as TEAEs are reported. |
Countries
Canada, France, Italy, Portugal, Spain, Switzerland, United States
Participant flow
Recruitment details
The trial was interrupted due to COVID-19 pandemic from 13Apr2020 to 07May2020.
Participants by arm
| Arm | Count |
|---|---|
| Durvalumab 1500 mg Participants received durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W; on Week 1 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection was planned between Day 29 and Day 42. After surgical resection, participants were followed up to Day 105 (starting from Week 1 Day 1). | 27 |
| Durvalumab 1500 mg + Oleclumab 3000 mg Participants received durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and oleclumab 3000 mg IV every 2 weeks (Q2W; on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection was planned between Day 29 and Day 42. After surgical resection, participants were followed up to Day 105 (starting from Week 1 Day 1). | 21 |
| Durvalumab 1500 mg + Monalizumab 750 mg Participants received durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and monalizumab 750 mg IV Q2W (on Week 1 Day 1 and Week 3 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection was planned between Day 29 and Day 42. After surgical resection, participants were followed up to Day 105 (starting from Week 1 Day 1). | 20 |
| Durvalumab 1500 mg + Danvatirsen 200 mg Participants received danvatirsen 200 mg IV on Days 1, 3, and 5 of Week 0 (7-day danvatirsen lead-in period), followed by durvalumab 1500 mg IV Q4W (on Week 1 Day 1) and danvatirsen 200 mg IV every week (on Week 1 Day 1, Week 2 Day 1, Week 3 Day 1, and Week 4 Day 1) until disease progression, unacceptable toxicity, or other reason of treatment discontinuation over a 28-day treatment period. Surgical resection was planned between Day 29 and Day 42. After surgical resection, participants were followed up to Day 105 (starting from Week 1 Day 1). | 16 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 |
| Overall Study | Other | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Durvalumab 1500 mg | Durvalumab 1500 mg + Oleclumab 3000 mg | Durvalumab 1500 mg + Monalizumab 750 mg | Durvalumab 1500 mg + Danvatirsen 200 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 67.1 Years STANDARD_DEVIATION 9 | 65.5 Years STANDARD_DEVIATION 7.5 | 65.1 Years STANDARD_DEVIATION 6.3 | 72.9 Years STANDARD_DEVIATION 7.9 | 67.3 Years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 21 Participants | 20 Participants | 14 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 23 Participants | 20 Participants | 19 Participants | 13 Participants | 75 Participants |
| Sex: Female, Male Female | 13 Participants | 9 Participants | 6 Participants | 6 Participants | 34 Participants |
| Sex: Female, Male Male | 14 Participants | 12 Participants | 14 Participants | 10 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 21 | 0 / 20 | 1 / 16 |
| other Total, other adverse events | 18 / 26 | 19 / 21 | 14 / 20 | 13 / 16 |
| serious Total, serious adverse events | 3 / 26 | 2 / 21 | 1 / 20 | 5 / 16 |
Outcome results
Primary
Major Pathological Response Rate
Major pathological response rate is defined as percentage of participants with \<=10% residual viable tumor cells in the resected specimen.
Time frame: Day 1 through Day 42
Population: The ITT population included participants who were randomized and were analyzed according to their randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab 1500 mg | Major Pathological Response Rate | 11.1 Percentage of participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Major Pathological Response Rate | 19.0 Percentage of participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Major Pathological Response Rate | 30.0 Percentage of participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Major Pathological Response Rate | 31.3 Percentage of participants |
Secondary
Feasibility to Surgery
Feasibility to surgery is defined as the percentage of participants who underwent the planned surgery within Days 29 to 42 after Week 1 Day 1.
Time frame: Day 29 to Day 42 after Week 1 Day 1
Population: As-treated population included all participants who received any study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab 1500 mg | Feasibility to Surgery | 84.6 Percentage of participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Feasibility to Surgery | 81.0 Percentage of participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Feasibility to Surgery | 90.0 Percentage of participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Feasibility to Surgery | 93.8 Percentage of participants |
Secondary
Number of Participants With Abnormal Vital Signs Reported as TEAEs
Participants with abnormal vital sign reported as TEAEs are reported.
Time frame: From Day 1 through Day 105
Population: As-treated population included all participants who received any study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Durvalumab 1500 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Palpitations | 1 Participants |
| Durvalumab 1500 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Pyrexia | 1 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Pyrexia | 2 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Palpitations | 0 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Palpitations | 0 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Pyrexia | 1 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Palpitations | 0 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Abnormal Vital Signs Reported as TEAEs | Pyrexia | 0 Participants |
Secondary
Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities
Participants with Grade 3 or Grade 4 clinical laboratory toxicities are reported. Laboratory tests included hematology, coagulation, chemistry, and urinalysis.
Time frame: From Day 1 through Day 105
Population: As-treated population included all participants who received any study drug and analyzed according to the treatment they actually received. 'Number Analyzed' denotes the participants analyzed for the specified laboratory parameters.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Durvalumab 1500 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Hyponatremia | 2 Participants |
| Durvalumab 1500 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Gamma glutamyl transferase increased | 0 Participants |
| Durvalumab 1500 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Lymphocyte count decreased | 0 Participants |
| Durvalumab 1500 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Lipase increased | 1 Participants |
| Durvalumab 1500 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Alanine aminotransferase increased | 0 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Lipase increased | 1 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Hyponatremia | 0 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Lymphocyte count decreased | 0 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Gamma glutamyl transferase increased | 0 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Alanine aminotransferase increased | 0 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Lipase increased | 1 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Alanine aminotransferase increased | 0 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Gamma glutamyl transferase increased | 0 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Hyponatremia | 0 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Lymphocyte count decreased | 0 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Hyponatremia | 0 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Gamma glutamyl transferase increased | 1 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Alanine aminotransferase increased | 2 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Lipase increased | 0 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Grade 3 or Grade 4 Clinical Laboratory Toxicities | Lymphocyte count decreased | 1 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.
Time frame: From Day 1 through Day 105
Population: As-treated population included all participants who received any study drug and analyzed according to the treatment they actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Durvalumab 1500 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 18 Participants |
| Durvalumab 1500 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 3 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 2 Participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 19 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 15 Participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 1 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TEAEs | 13 Participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | Any TESAEs | 5 Participants |
Secondary
Pathological Complete Response (pCR) Rate
The pCR rate is defined as percentage of participants with no residual viable tumor cells in the resected specimen.
Time frame: Day 1 through Day 42
Population: The ITT population included participants who were randomized and were analyzed according to their randomized treatment group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Durvalumab 1500 mg | Pathological Complete Response (pCR) Rate | 3.7 Percentage of participants |
| Durvalumab 1500 mg + Oleclumab 3000 mg | Pathological Complete Response (pCR) Rate | 9.5 Percentage of participants |
| Durvalumab 1500 mg + Monalizumab 750 mg | Pathological Complete Response (pCR) Rate | 10.0 Percentage of participants |
| Durvalumab 1500 mg + Danvatirsen 200 mg | Pathological Complete Response (pCR) Rate | 12.5 Percentage of participants |