Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Afatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

once daily afatinib at a dose of 40 mg for 8 weeks followed by surgery with curative intent (anatomical resection and systematic lymph node dissection).

immediate surgery with curative intent (anatomical resection and systematic lymph node dissection).

once daily afatinib at a dose of 40 mg for 8 weeks

anatomical resection and systematic lymph node dissection

Immediate surgery

Sanjay Popat, PhD

This is a multicenter, randomized, 1:1, non-comparative phase II trial. Patients with early stage NSCLC will be randomized between ARM A: neoadjuvant afatinib followed by surgery and ARM B: immediate surgery with curative intent.

This is a multicenter, prospective, open-label, randomized, non-comparative, two-arm phase II trial aiming to evaluate afatinib treatment in pre-operative setting in patients with EGFR mutated NSCLC.

After signing of the informed consent, patients will be registered and screened for eligibility and upon confirmation of all eligibility criteria, patients will be randomized 1:1 to:

* Arm A: once daily afatinib at a dose of 40 mg for 8 weeks followed by surgery with curative intent (anatomical resection and systematic lymph node dissection).
* Arm B: immediate surgery with curative intent (anatomical resection and systematic lymph node dissection).

Response evaluation in the pre-operative arm will be performed through CT scans at baseline, 4 and 8 weeks.

The first 5 patients enrolled in arm A will be part of a safety run-in to check that afatinib treatment doesn't delay surgery.

Neoadjuvant Afatinib in Early Stage Non Small Cell Lung Cancer.

Resectable EGFR Mutant NSCLC With (or Without) Afatinib as Neoadjuvant Treatment; REMNANT an Exploratory Study of the EORTC Lung Cancer Group

decrease in cT-stage descriptor measured according to RECIST 1.1

proportion of patients whose response is either complete response (CR) or partial response (PR) using RECIST 1.1;

European Organisation for Research and Treatment of Cancer - EORTC

Osimertinib

Immunomodulating Agents

Mitogens

In Part 1 (dose-escalation), participants will receive intravenous oleclumab (MEDI9447) Dose 1 every 2 weeks (Q2W) and oral osimertinib Dose 1 once daily (QD).

In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD. In Part 2 (dose-expansion), participants (including participants dosed at the RP2D in Part 1) will receive IV oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD until documentation of disease progression, intolerable toxicity, or development of other reason for treatment discontinuation, whichever occurs first.

In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 1 QD.

In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 2 QD.

In Part 1 (dose-escalation), participants will receive intravenous oleclumab Dose 2 Q2W and oral AZD4635 Dose 2 QD.

Participants will receive oleclumab in combination with osimertinib or AZD4635 as stated in the arms' description.

Oleclumab

Participants will receive osimertinib in combination with oleclumab as stated in the arms' description.

Participants will receive AZD4635 in combination with oleclumab as stated in the arms' description.

AZD4635

MedImmune LLC

The objective of this study is to investigate the safety, tolerability, and antitumor activity of novel combination therapies administered in participants with advanced EGFRm NSCLC.

Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study

A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to Evaluate Novel Combination Therapies in Subjects With Previously Treated Advanced EGFRm NSCLC

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

A DLT was defined as \>= Grade 3 toxicity or adverse events (AE) occurred during DLT evaluation period which included any Grade 4 immune-mediated (immune nature) AE, anemia, thrombocytopenia (present \> 4 days), or neutropenia (present \> 4 days); \>= Grade 3 colitis or pneumonitis or interstitial lung disease (ILD); \>= Grade 3 nausea, vomiting, or diarrhea (not resolved to \<= Grade 2 in 3 days); Grade 2 pneumonitis or ILD (not resolved to \<= Grade 1 in 3 days); Grade 3 thrombocytopenia with bleeding, any grade febrile neutropenia; convulsions, seizures, or stroke; protocol defined elevations of isolated liver transaminase, isolated total bilirubin (TBL), or Hy's Law; confirmed QT interval corrected for heart rate by Fridericia's formula prolongation (\>= 501 msec) on triplicate electrocardiograms within a short period of time; or any other toxicity greater than that at baseline, was clinically significant and/or unacceptable, and was judged to be a DLT by the Dose Escalation Committee.

An 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.

Participants with abnormal laboratory parameters reported as TEAEs are reported. Laboratory analysis included hematology, clinical chemistry, thyroid function tests, and urinalysis.

Participants with abnormal vital signs (heart rate, blood pressure, temperature, and respiratory rate) and physical examination reported as TEAEs are reported.

Notable QTc intervals included single beat changes from baseline (Day 1) values (\> 30, \> 60, and \> 90 milliseconds). Participants who had notable QTc interval are reported.

The OR is defined as confirmed complete response (CR) or confirmed partial response (PR) based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between.

The DoR is defined as duration from the first documentation of OR (confirmed CR or PR) to the first documented disease progression based on RECIST v1.1 guidelines or death due to any cause, whichever occurs first. A CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. A PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. The progressive disease is defined at least a 20% increase in sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. The DoR was analyzed using Kaplan-Meier method.

The DC is defined as percentage of participants with CR, PR, or stable disease (SD, which was maintained by \>= 8 week) based on RECIST v1.1 guidelines. A CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. A PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum longest diameter since the study treatment started, and non-progressive disease and not evaluable or no non-target lesion.

The PFS is defined as the time from the start of study treatment until the documentation of disease progression based on RECIST version 1.1 or death due to any cause, whichever occurs first, regardless of whether the participant received subsequent anticancer treatment prior to progression. The progressive disease is defined at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started, the appearance of one or more new lesions, or unequivocal progression of existing non-target lesions. Participants who were alive and progression-free at the time of data cut-off for analysis had PFS censored at the last tumor assessment date. The PFS was estimated using Kaplan-Meier method.

The OS is defined as the time from the start of study treatment until death due to any cause. Participants who are alive at the time of data cut-off had OS censored at the last known to be alive date. The OS was estimated using Kaplan-Meier method.

The T790M status was determined by plasma testing in a central laboratory at Baseline (Days -28 to -1). The OR is defined as confirmed CR or confirmed PR based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as \>= 30% decrease in the sum of the diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. A confirmed CR or PR is defined as 2 CRs or 2 PRs that were separated by at least 4 weeks with no evidence of progression in-between. Cell-free circulating tumor deoxyribonucleic acid (ctDNA) from liquid biopsy was used as a surrogate marker for T790M status in tumor tissue.

The T790M status was determined by plasma testing in a central laboratory at Baseline (Days -28 to -1). The DC is defined as percentage of participants with CR, PR, or SD (maintained by \>= 8 week) based on RECIST v1.1 guidelines. A CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. A PR is defined as \>= 30% decrease in the sum of longest diameters of target lesions compared to baseline, and non-progressive disease and not evaluable or no non-target lesion. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum longest diameter since the study treatment started, and persistence of one or more non-target lesion(s). Cell-free circulating tumor deoxyribonucleic acid (ctDNA) from liquid biopsy was used as a surrogate marker for T790M status in tumor tissue.

The Cmax of osimertinib and AZ5104 are reported.

The Cmax of AZD4635, SSP-005173X, and SSP-005174X are reported.

The Tmax of AZD4635, SSP-005173X, and SSP-005174X are reported.

The AUC0-24 of AZD4635, SSP-005173X, and SSP-005174X are reported.

Number of participants with positive post-baseline for anti-oleclumab antibodies are reported.

In Part 1 (dose-escalation), participants received intravenous oleclumab (MEDI9447) Dose 1 every 2 weeks (Q2W) and oral osimertinib Dose 1 once daily (QD).

Oleclumab Dose 1 + Osimertinib Dose 1

In Part 1 (dose-escalation), participants received intravenous oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD. In Part 2 (dose-expansion), participants (including participants dosed at the RP2D in Part 1) received IV oleclumab Dose 2 Q2W and oral osimertinib Dose 1 QD until documentation of disease progression, intolerable toxicity, or development of other reason for treatment discontinuation, whichever occurred first.

Oleclumab Dose 2 + Osimertinib Dose 1

In Part 1 (dose-escalation), participants received intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 1 QD.

Oleclumab Dose 1 + AZD4635 Dose 1

In Part 1 (dose-escalation), participants received intravenous oleclumab Dose 1 Q2W and oral AZD4635 Dose 2 QD.

Oleclumab Dose 1 + AZD4635 Dose 2

In Part 1 (dose-escalation), participants received intravenous oleclumab Dose 2 Q2W and oral AZD4635 Dose 2 QD.

Oleclumab Dose 2 + AZD4635 Dose 2

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

As-treated population included all participants who received any study drug and were analyzed according to the treatment they actually received.

Arm B (Oleclumab + AZD4635 groups) did not proceed to the dose expansion phase due to lack of response to treatment and a change in the formulation of AZD4635. The OR and DC by T790M status for 'Oleclumab + AZD4635' groups were not conducted due to the small sample size.

Global Clinical Lead

The DLT-evaluable population included all participants who enrolled in the dose-escalation phase, received all planned doses of oleclumab and at least 75% of the daily administrations of osimertinib or AZD4635 during the DLT-evaluation period and completed the safety follow-up through the DLT-evaluation period or experienced any DLTs.

Number of Participants With Dose-limiting Toxicities (DLTs) in Part 1

Any TEAEs

Any TESAEs

Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) in Parts 1 and 2

Anaemia

Neutropenia

Alanine aminotransferase increased

Amylase increased

Aspartate aminotransferase increased

Blood alkaline phosphatase increased

Blood creatinine increased

Lipase increased

Hypercholesterolaemia

Hyperglycaemia

Hyperkalaemia

Hypoalbuminaemia

Hypocalcaemia

Hypokalaemia

Hypomagnesaemia

Hyponatraemia

Hypophosphataemia

Leukopenia

Blood albumin decreased

Haemoglobin decreased

Neutrophil count decreased

White blood cell count decreased

Hypercalcaemia

Thrombocytopenia

Hypothyroidism

Blood creatine phosphokinase increased

Platelet count decreased

Number of Participants With Abnormal Laboratory Parameters Reported as TEAEs in Parts 1 and 2

Hypertension

Hypotension

Pyrexia

Hypoxia

Number of Participants With Abnormal Vital Signs and Physical Examination Reported as TEAEs in Parts 1 and 2

Single Beat change from baseline, Change > 30 milliseconds

Single Beat change from baseline, Change > 60 milliseconds

Single Beat change from baseline, Change > 90 milliseconds

Number of Participants With Notable QTc Interval in Parts 1 and 2

Percentage of Participants With Objective Response (OR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 in Part 2

As-treated population included all participants who received any study drug and were analyzed according to the treatment they actually received. The DoR was analyzed for participants who achieved OR.

Duration of Response (DoR) Per RECIST v 1.1 for Parts 1 and 2

Percentage of Participants With Disease Control (DC) in Parts 1 and 2

Progression Free Survival (PFS) for Parts 1 and 2

Overall Survival (OS) for Parts 1 and 2

OR by T790M status positive

OR by T790M status negative

As-treated population included all participants who received any study drug and were analyzed according to the treatment they actually received. 'Number of participants analyzed' denotes participants who had T790M status positive or negative at baseline (Days -28 to -1). The T790M status results was assessed only for participants in 'Oleclumab + Osimertinib' arms.

Percentage of Participants With OR by T790M Status at Baseline (Determined by a Central Laboratory) for Parts 1 and 2

DC by T790M status positive

DC by T790M status negative

As-treated population included all participants who received any study drug and were analyzed according to the treatment they actually received. 'Number of participants analyzed' denotes participants who had T790M status positive or negative at baseline (Days -28 to -1).

Percentage of Participants With DC by T790M Status at Baseline (Determined by a Central Laboratory) for Parts 1 and 2

Day 1

Day 57

Pharmacokinetic (PK) population included all participants who received any study drug, analyzed according to the treatment they actually received, and had at least one quantifiable post-dose concentration with no important protocol deviations or AEs considered to impact the PK data. 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Observed Serum Concentration at the Time of End of Infusion (CEOI) of Oleclumab (MEDI9447) Over Time

The PK population included all participants who received any study drug, analyzed according to the treatment they actually received, and had at least one quantifiable post-dose concentration with no important protocol deviations or AEs considered to impact the PK data. ''Number of participants analyzed' denotes the number of participants who had adequate PK sample and were evaluated for this outcome measure.

Observed Lowest Serum Concentration (Ctrough) of MEDI9447 Over Time

Osimertinib, Day 1

Osimertinib, Day 29

AZ5104, Day 1

AZ5104, Day 29

The PK population included all participants who received any study drug, analyzed according to the treatment they actually received, and had at least one quantifiable post-dose concentration with no important protocol deviations or AEs considered to impact the PK data. 'Number of participants analyzed' denotes the number of participants evaluated for this outcome measure. 'Number analyzed' denotes the number of participants evaluated for the specified time point.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Neoadjuvant Afatinib in Early Stage Non Small Cell Lung Cancer.	NCT02470065	Non Small Cell ...	Afatinib Immediate surge...	18 Years - 90 Years	European Organisation for Research and Treatment of Cancer - EORTC
Oleclumab (MEDI9447) Epidermal Growth Factor Receptor Mutant (EGFRm) Non-small Cell Lung Cancer (NSCLC) Novel Combination Study	NCT03381274	Carcinoma, Non-...	Oleclumab Osimertinib AZD4635	18 Years - 101 Years	MedImmune LLC

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