MEDI9447(Oleclumab) Pancreatic Chemotherapy Combination Study.

MedImmune LLC213 enrolled

Overview

The objective of this study is to evaluate the safety, tolerability, and antitumor activity of oleclumab (MEDI9447) in combination with or without durvalumab plus chemotherapy in participants with metastatic pancreatic cancer.

This is a Phase 1b/2, multicenter, open-label, dose-escalation, and dose-expansion study to assess the safety, preliminary antitumor activity, immunogenicity, and pharmacokinetics (PK) of oleclumab with or without durvalumab in combination with chemotherapy administered in participants with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants with previously untreated metastatic PDAC (first-line \[1L\] metastatic PDAC) will be enrolled in Cohort A. Participants with metastatic PDAC previously treated with gemcitabine-based chemotherapy (without exposure to 5-fluorouracil \[5-FU\], capecitabine, or oxaliplatin; second-line \[2L\] metastatic PDAC) will be enrolled in Cohort B. The study consists of 2 parts, dose escalation (Part 1) and dose expansion (Part 2).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

213

Conditions

Carcinoma Metastatic Pancreatic Adenocarcinoma

Interventions

OleclumabDRUG

Participants will receive IV infusion of oleclumab as stated in arm description.

DurvalumabDRUG

Participants will receive IV infusion of durvalumab as stated in arm description.

GemcitabineDRUG

Participants will receive IV infusion of gemcitabine as stated in arm description.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 101 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age \>= 18 2. Written and signed informed consent must be obtained 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 4. Weight \>= 35 kg 5. Participants must have histologically or cytologically, confirmed pancreatic adenocarcinoma: Cohort A: Participants with previously untreated metastatic pancreatic adenocarcinoma (1L metastatic disease) not previously treated with systemic therapies Cohort B: Participants with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based chemotherapy (without exposure to 5-FU, capecitabine, oxaliplatin) 2L metastatic disease 6. Participants must have at least 1 measurable lesion according to RECIST v1.1 7. All Participants must consent to providing archival tumor specimens. Exclusion Criteria: 1. Receipt of any conventional or investigational anticancer therapy within 21 days or palliative radiotherapy within 14 days prior to the scheduled first dose of study treatment. 2. Prior receipt of any immune-related therapy 3. Concurrent enrollment in another therapeutic clinical study. Enrollment in observational studies will be allowed. 4. Participants with a history of venous thrombosis within the past 3 months 5. Participants with prior history of myocardial infarction, transient ischemic attack, or stroke in the last 3 months prior to start of treatment 6. Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment 7. Other invasive malignancy within 2 years 8. Any history of leptomeningeal disease or cord compression 9. Current or prior use of immunosuppressive medication within 14 days prior to the first dose.

Locations (27)

Research Site

La Jolla, California, United States

Outcomes

Primary Outcomes

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) in Dose Escalation Phase

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: Day 1 through 65.7 weeks (maximum observed duration)

Number of Participants With Dose-limiting Toxicities (DLTs) in Dose Escalation Phase

DLT: Any study drug related Grade (G)3 or higher toxicity including: any G4 immune-mediated AEs, \>=G3 colitis/pneumonitis/interstitial lung disease (ILD), \>=G3 nausea/vomiting/diarrhea that does not resolve to G2 or less within 3 days of maximal supportive care (MSC), G2 pneumonitis/ILD that does not resolve within 7 days of initiation of MSC, G4 anemia, G3 anemia with clinical sequelae/requires \>2 units of red blood cells transfusion, G4 thrombocytopenia/neutropenia \>=7 days, G3/4 thrombocytopenia with \>=G3 hemorrhage, G4 febrile neutropenia (FN), G3 FN lasting \>=5 days while receiving MSC, isolated G3 liver transaminase elevation (LTE)/ isolated G3 total bilirubin (TBL) that does not downgrade to G1 or less within 14 days of onset, isolated G4 LTE or TBL, elevated aspartate aminotransferase/alanine aminotransferase \>3×upper limit of normal (ULN) and concurrent TBL \>2×ULN without cholestasis or alternative explanations, any other toxicity judged as a DLT by Dose Escalation Committee.

Time frame: From Day 1 to 28 days after the first dose of study drugs

Number of Participants With Abnormal Vital Signs Reported as TEAEs in Dose Escalation Phase

Number of participants with abnormal vital signs (temperature, blood pressure, pulse rate, and respiratory rate) reported as TEAEs are reported.

Time frame: Day 1 through 65.7 weeks (maximum observed duration)

Data from ClinicalTrials.gov

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Secondary Outcomes

Number of Participants With TEAEs and TESAEs in Dose Expansion Phase

An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An 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: Day 1 through 172.1 weeks (maximum observed duration)

Number of Participants With Abnormal Vital Signs Reported as TEAEs in Dose Expansion Phase

Number of participants with abnormal vital signs (temperature, blood pressure, pulse rate, and respiratory rate) reported as TEAEs are reported.

Time frame: Day 1 through 172.1 weeks (maximum observed duration)

Number of Participants With Abnormal ECG Parameters Reported as TEAEs in Dose Expansion Phase

Number of participants with abnormal ECG parameters reported as TEAEs are reported.

Time frame: Day 1 through 172.1 weeks (maximum observed duration)

Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs in Dose Expansion Phase

Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.

Time frame: Day 1 through 172.1 weeks (maximum observed duration)

Percentage of Participants With OR According to RECIST v1.1 in Dose Escalation Phase

The OR is defined as best overall response of confirmed CR or confirmed PR based on RECIST v1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions, any pathological lymph nodes (target and non-target) must have reduction in short axis \< 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. Percentage of participants with OR is reported.

Time frame: Baseline (Days -28 to -1) through 24.5 months (maximum observed duration)

Percentage of Participants With Disease Control (DC) According to RECIST v1.1 in Dose Escalation Phase

The DC is defined as confirmed CR, PR, or stable disease (SD) (maintained for \>=8 weeks). The CR is defined as disappearance of all TLs and NTLs, any pathological lymph nodes (target and non-target) must have reduction in short axis \<10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from date of first documentation. The SD is defined as neither sufficient shrinkage of TLs to qualify for PR nor sufficient increase of TLs to qualify for progressive disease (PD), taking as reference the smallest SoD while on study, and no new lesions. The PD is defined as at least a 20% increase in SoD of TLs, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of SoD, or unequivocal progression of existing NTLs, or the appearance of new lesion/s. Percentage of participants with DC is reported.

Time frame: Baseline (Days -28 to -1) through 24.5 months (maximum observed duration)

Number of Participants With Overall Survival Events in Dose Expansion Phase

Time frame: Baseline (Days -28 to -1) through 38.7 months (maximum observed duration)

Overall Survival in Dose Expansion Phase

Time frame: Baseline (Days -28 to -1) through 38.7 months (maximum observed duration)

Number of Participants With Progression-free Survival Events According to RECIST v1.1 in Dose Expansion Phase

Progression-free survival (PFS) is defined as the time from randomization until the first documentation of a PD or death due to any cause, whichever occurred first, regardless of whether the participant received subsequent anticancer treatment prior to progression. The PD is defined as at least a 20% increase in sum of the diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of sum of the diameters, or unequivocal progression of existing non-target lesions, or the appearance of new lesion/s. Participants who had no documented progression and were still alive at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST v1.1 assessment. The PFS is assessed using the Kaplan-Meier method. The number of participants with PFS events is reported.

Time frame: Baseline (Days -28 to -1) through 36.1 months (maximum observed duration)

Progression-free Survival According to RECIST v1.1 in Dose Expansion Phase

The PFS is defined as the time from randomization until the first documentation of a PD or death due to any cause, whichever occurred first, regardless of whether the participant received subsequent anticancer treatment prior to progression. The PD is defined as at least a 20% increase in sum of the diameters of target lesions, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of sum of the diameters, or unequivocal progression of existing non-target lesions, or the appearance of new lesion/s. Participants who had no documented progression and were still alive at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST v1.1 assessment. The PFS is assessed using the Kaplan-Meier method.

Time frame: Baseline (Days -28 to -1) through 36.1 months (maximum observed duration)

Duration of Response (DoR) According to RECIST v1.1 in Dose Expansion Phase

The DoR is defined as the time from the first documentation of an OR until the first documentation of a PD or death due to any cause, whichever occurs first. The OR is defined as best overall response of confirmed CR or PR based on RECIST v1.1 guidelines. The CR is defined as disappearance of all TLs and NTLs, any pathological lymph nodes (target and non-target) must have reduction in short axis \< 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in SoD of TLs, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of SoD, or unequivocal progression of existing NTLs, or the appearance of new lesion/s. The DoR is assessed using the Kaplan-Meier method.

Time frame: Baseline (Days -28 to -1) through 36.1 months (maximum observed duration)

Percentage of Participants With DC According to RECIST v1.1 in Dose Expansion Phase

The DC is defined as confirmed CR, PR, or stable disease (SD) (maintained for \>=8 weeks). The CR is defined as disappearance of all TLs and NTLs, any pathological lymph nodes (target and non-target) must have reduction in short axis \<10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from date of first documentation. The SD is defined as neither sufficient shrinkage of TLs to qualify for PR nor sufficient increase of TLs to qualify for PD, taking as reference the smallest SoD while on study, and no new lesions. The PD is defined as at least a 20% increase in SoD of TLs, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of SoD, or unequivocal progression of existing NTLs, or the appearance of new lesion/s. Percentage of participants with DC is reported.

Time frame: Baseline (Days -28 to -1) through 36.1 months (maximum observed duration)

Percentage of Participants With OR According to RECIST v1.1 by CD73 Expression at Baseline in Dose Expansion Phase

The OR is defined as best overall response of confirmed CR or confirmed PR based on RECIST v1.1. The CR is defined as disappearance of all TLs and NTLs, any pathological lymph nodes (target and non-target) must have reduction in short axis \<10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The OR is assessed by cluster of differentiation 73 (CD73) expression level either low or high at baseline. The CD73 low is defined as no CD73 expression in tumor cells or \<50% of tumor cells with 2+ or 3+ intensity and CD73 high is defined as CD73 expression with 2+ or 3+ intensity in \>=50% of tumor cells.

Time frame: Baseline (Days -28 to -1) through 36.1 months (maximum observed duration)

Number of Participants With Overall Survival Events by CD73 Expression at Baseline in Dose Expansion Phase

The overall survival is defined as the time from the randomization until death due to any cause. For participants who were alive at the time of data cut off, overall survival was censored on the last date when participants were known to be alive. The overall survival is assessed by CD73 expression level either low or high at baseline using the Kaplan-Meier method. The CD73 low is defined as no CD73 expression in tumor cells or \<50% of tumor cells with 2+ or 3+ intensity and CD73 high is defined as CD73 expression with 2+ or 3+ intensity in \>=50% of tumor cells. The number of participants with overall survival events (deaths) is reported.

Time frame: Baseline (Days -28 to -1) through 38.7 months (maximum observed duration)

Overall Survival by CD73 Expression at Baseline in Dose Expansion Phase

Time frame: Baseline (Days -28 to -1) through 38.7 months (maximum observed duration)

Number of Participants With Progression-free Survival Events According to RECIST v1.1 by CD73 Expression at Baseline in Dose Expansion Phase

PFS: Time from randomization until first documentation of PD/death due to any cause, whichever occurred first, regardless of whether participant received subsequent anticancer treatment prior to progression. PD:\>=20% increase in SoD of TLs and an absolute increase of \>= 5 mm of SoD/unequivocal progression of existing NTLs/appearance of new lesion. Participants who had no documented progression and were still alive at the time of analysis were censored at time of latest date of assessment from their last evaluable RECIST v1.1 assessment. PFS is assessed by CD73 expression level either low/high at baseline using Kaplan-Meier method. CD73 low: No CD73 expression in tumor cells/\<50% of tumor cells with 2+/3+ intensity. CD73 high: CD73 expression with 2+/3+ intensity in \>=50% of tumor cells. Number of participants with PFS events is reported.

Time frame: Baseline (Days -28 to -1) through 36.1 months (maximum observed duration)

Progression-free Survival According to RECIST v1.1 by CD73 Expression at Baseline in Dose Expansion Phase

The PFS is defined as the time from randomization until the first documentation of a PD or death due to any cause, whichever occurred first, regardless of whether the participant receives subsequent anticancer treatment prior to progression. The PD is defined as at least a 20% increase in SoD of TLs, taking as reference the smallest sum on study and an absolute increase of at least 5 mm of SoD, or unequivocal progression of existing NTLs, or the appearance of new lesion/s. Participants who had no documented progression and were still alive at time of analysis were censored at time of latest date of assessment from their last evaluable RECIST v1.1 assessment. PFS is assessed by CD73 expression level either low/high at baseline using Kaplan-Meier method. CD73 low: No CD73 expression in tumor cells/\<50% of tumor cells with 2+/3+ intensity. CD73 high: CD73 expression with 2+/3+ intensity in \>=50% of tumor cells.

Time frame: Baseline (Days -28 to -1) through 36.1 months (maximum observed duration)

Number of Participants With Positive Anti-drug Antibodies (ADA) to Oleclumab

Number of participants with positive ADA to oleclumab are reported. Persistent positive is defined as positive at \>= 2 post-baseline assessments (with \>=16 weeks between first and last positive) or positive at last post-baseline assessment. Transient positive is defined as negative at last post-baseline assessment and positive at only one post-baseline assessment or at \>= 2 post-baseline assessments (with \<16 weeks between first and last positive). Treatment-boosted ADA is defined as baseline ADA positive titer that was boosted to a 4-fold or higher level following drug administration.

Time frame: Day 1 through 172.1 weeks (Pre-dose on Cycle [C] 1 Day [D] 1, C2D1, C3D1, Day 1 of every 3 cycles starting with C5, through 12 weeks post last dose of oleclumab)

Number of Participants With Positive ADA to Durvalumab

Number of participants with positive ADA to durvalumab are reported. Persistent positive is defined as positive at \>= 2 post-baseline assessments (with \>=16 weeks between first and last positive) or positive at last post-baseline assessment. Transient positive is defined as negative at last post-baseline assessment and positive at only one post-baseline assessment or at \>= 2 post-baseline assessments (with \<16 weeks between first and last positive). Treatment-boosted ADA is defined as baseline ADA positive titer that was boosted to a 4-fold or higher level following drug administration.

Time frame: Day 1 through 128 weeks (Pre-dose on C1D1, C2D1, C3D1, Day 1 of every 3 cycles starting with C5, through 12 weeks post last dose of durvalumab)

Serum Concentrations of Oleclumab

Serum concentrations of oleclumab are reported.

Time frame: Ten minutes (mins) (± 5 mins) post end of infusion (EOI), approximately 1 hour (+ 15 mins) after start of infusion on C1D1, C3D1, and C5D1; and pre-dose on C3D1 and C5D1

Serum Concentrations of Durvalumab

Serum concentrations of durvalumab are reported.

Time frame: Ten mins (± 5 mins) post EOI, approximately 1 hour (+ 15 mins) after start of infusion on C1D1 and C5D1; and pre-dose on C2D1 and C5D1

Plasma Concentrations of Gemcitabine and Metabolite 2',2'-Difluorodeoxyuridine (dFdU)

Plasma concentrations of gemcitabine and metabolite dFdU are reported.

Time frame: Ten mins (± 5 mins) post EOI, approximately 30-40 mins after start of infusion on C1D1 and C4D1; and pre-dose on C4D1

Plasma Concentrations of Nab-paclitaxel

Plasma concentrations of nab-paclitaxel are reported.

Time frame: Ten mins (± 5 mins) post EOI, approximately 30-40 mins after start of infusion on C1D1 and C4D1; and pre-dose on C4D1