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NCT02109445

Study Of PF-03084014 In Combination With Gemcitabine And Nab-Paclitaxel In Patients With Metastatic Pancreatic Adenocarcinoma Not Previously Treated With Anticancer Therapies

Terminated Phase 2 Results posted Last updated 10 January 2019
What this trial tests

Phase 2 trial testing PF-03084014 in Metastatic Cancer Pancreas in 3 participants. Terminated before completion.

Timeline
3 September 2014
Primary endpoint
6 November 2014
6 November 2014

Quick facts

Lead sponsorPfizer
PhasePhase 2
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Maskingnone
Primary purposetreatment
Enrollment3
Start date3 September 2014
Primary completion6 November 2014
Estimated completion6 November 2014
Sites5 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Pfizer — full company profile →

Who can join

18 and older, any sex, with Metastatic Cancer Pancreas. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1 Primary · Cycle 1 (28 days)

DLT was defined as any of the following events occurring during the first cycle of treatment and considered at least possibly-related to study medication: any Grade 3 or 4 clinically-relevant non-hematologic and/or hematologic toxicity, delay of more than 2 weeks in receiving the next scheduled cycle due to persisting treatment-related toxicities.

GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine2
Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 Secondary · Baseline up to 28-35 days post last administration of study drug

Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. Severity was graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Grade 1=mild, Grade 2=moderate, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=life-threatening.

All-causality TEAEs
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine3
Treatment-related TEAEs
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine3
Grade 3 or 4 TEAEs
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine3
Number of Participants With Laboratory Abnormalities in Phase 1 Secondary · Screening; Cycle 1 Days 1, 8, 15, 22; up to 28-35 days post last administration of study drug

Following parameters were analyzed for laboratory examination: hematology (hemoglobin, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (urea, creatinine, glucose, calcium, sodium, potassium, chloride, magnesium, phosphate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid); urinalysis (protein, blood, microscopy\[if urine tested positive for blood or protein\]).

GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine3
Number of Participants With Worsening QTc Results in Phase 1 Secondary · Screening, Cycle 1 Days 3 and 22, Cycles 2 and 3 Day 1, end of treatment

Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) were corrected for heart rate (QTc) using Fridericia (QTcF) and Bazett (QTcB) formulas. Any change from baseline in QTc was considered as worsening in ECG and was classified accordingly to the Common Terminology Criteria (CTC) grade. Grading was as follows: prolonged QTc of 450 to 480 milliseconds (msec)=Grade 1, 481 to 500 msec=Grade 2, mor

GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + GemcitabineNA
Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 Secondary · PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15.

AUC included AUC from time 0 extrapolated to infinite time (AUCinf), AUC from time 0 to end of dosing interval (AUCtau, tau=12 hours), and AUC from time 0 to last measured concentration (AUClast).

AUClast for PF-03084014 on Day 3 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine1122± 913
AUClast for PF-03084014 on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine1770± NA
AUCinf for nab-paclitaxel on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine5774± 11
AUClast for nab-paclitaxel on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine5185± 9
AUCinf for nab-paclitaxel on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine5050± NA
AUClast for nab-paclitaxel on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine4600± NA
AUCinf for gemcitabine on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine5316± 172
AUClast for gemcitabine on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine5262± 176
Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 Secondary · PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15.
Cmax for PF-03084014 on Day 3 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine527.3± 710
Cmax for PF-03084014 on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine943.0± NA
Cmax for nab-paclitaxel on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine6023± 6
Cmax for nab-paclitaxel on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine5140± NA
Cmax for gemcitabine on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine10760± 212
Cmax for gemcitabine on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine3620± NA
Systemic Clearance (CL) of Nab-paclitaxel in Phase 1 Secondary · Cycle 1 Days 1-3, and 15-17
Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine37.88± 25
Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine38.60± NA
Systemic Clearance (CL) of Gemcitabine in Phase 1 Secondary · Cycle 1 Days 1 and 15
Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine5.434± 165
Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine8.160± NA
Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 Secondary · PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15.
Tmax of PF-03084014 on Day 3 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine1.230.517 – 4.13
Tmax of PF-03084014 on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine0.900NA – NA
Tmax of nab-paclitaxel on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine0.5500.517 – 0.583
Tmax of nab-paclitaxel on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine0.217NA – NA
Tmax of gemcitabine on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine0.5170.250 – 0.533
Tmax of gemcitabine on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine0.350NA – NA
Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1 Secondary · Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel)
Vss of nab-paclitaxel on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine64.46± 6
Vss of nab-paclitaxel on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine60.80± NA
Vss of gemcitabine on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine61.76± 186
Vss of gemcitabine on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine201.0± NA
Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1 Secondary · Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel)
t1/2 of nab-paclitaxel on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine2.500± 0.26851
t1/2 of nab-paclitaxel on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine2.030± NA
t1/2 of gemcitabine on Day 1 (n=3)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine0.2813± 0.14838
t1/2 of gemcitabine on Day 15 (n=1)
GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine0.2230± NA
Number of Participants With Objective Response (OR) in Phase 1 Secondary · Screening till 28-35 days post last administration of study drug

Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than (\<) 10 mm). No new lesions. PR was defined as more than or equal to (\>=) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, w

GroupValue95% CI
PF-03084014 + Nab-Paclitaxel + Gemcitabine0

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline through and including 28 calendar days after the last administration of the investigational product.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

PF-03084014+Nab-Paclitaxel+Gemcitabine
Serious: 2/3 (67%)
Deaths:

Serious adverse events (4 terms)

ReactionSystemPF-03084014+Nab-Paclitaxel…
VomitingGastrointestinal disorders
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
Pulmonary embolismRespiratory, thoracic and mediastinal disorders
Other adverse events (22 terms — click to expand)

ReactionSystemPF-03084014+Nab-Paclitaxel…
FatigueGeneral disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
AscitesGastrointestinal disorders
ChillsGeneral disorders
Mucosal inflammationGeneral disorders
Candida infectionInfections and infestations
FallInjury, poisoning and procedural complications
Blood bilirubin increasedInvestigations
Decreased appetiteMetabolism and nutrition disorders
Failure to thriveMetabolism and nutrition disorders
HypokalaemiaMetabolism and nutrition disorders
HypophosphataemiaMetabolism and nutrition disorders
DizzinessNervous system disorders
AnxietyPsychiatric disorders
DepressionPsychiatric disorders
HallucinationPsychiatric disorders
CoughRespiratory, thoracic and mediastinal disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
RashSkin and subcutaneous tissue disorders

Most-reported serious reactions: Vomiting, Alanine aminotransferase increased, Aspartate aminotransferase increased, Pulmonary embolism.

Data from ClinicalTrials.gov NCT02109445 adverse events section.

Sponsor's own description

This study consists of a Phase 1b portion aimed to determine the maximum tolerated dose and the safety profile of PF-03084014 in combination with gemcitabine and nab-paclitaxel followed by a Phase 2 portion to evaluate the efficacy of the triple combination in terms of overall survival in patients with metastatic pancreatic ductal adenocarcinoma not previously treated with anticancer therapies.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Targeting cancer stem cell pathways for cancer therapy.
    Yang L, Shi P, Zhao G, Xu J, et al · · 2020 · cited 1354× · PMID 32296030 · DOI 10.1038/s41392-020-0110-5
  2. Emerging agents that target signaling pathways in cancer stem cells.
    Yang Y, Li X, Wang T, Guo Q, et al · · 2020 · cited 111× · PMID 32456660 · DOI 10.1186/s13045-020-00901-6
  3. Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives.
    Moore G, Annett S, McClements L, Robson T. · · 2020 · cited 85× · PMID 32575680 · DOI 10.3390/cells9061503
  4. Cancer Stem Cells: Emerging Key Players in Immune Evasion of Cancers.
    Lei MML, Lee TKW. · · 2021 · cited 84× · PMID 34235155 · DOI 10.3389/fcell.2021.692940
  5. Cancer of the Pancreas: Molecular Pathways and Current Advancement in Treatment.
    Polireddy K, Chen Q. · · 2016 · cited 68× · PMID 27471566 · DOI 10.7150/jca.14922
  6. Therapeutic Targeting of Notch Signaling: From Cancer to Inflammatory Disorders.
    Allen F, Maillard I. · · 2021 · cited 62× · PMID 34124039 · DOI 10.3389/fcell.2021.649205
  7. Metastatic pancreatic cancer: Is there a light at the end of the tunnel?
    Vaccaro V, Sperduti I, Vari S, Bria E, et al · · 2015 · cited 49× · PMID 25944992 · DOI 10.3748/wjg.v21.i16.4788
  8. The role of Hedgehog and Notch signaling pathway in cancer.
    Xia R, Xu M, Yang J, Ma X. · · 2022 · cited 39× · PMID 36517618 · DOI 10.1186/s43556-022-00099-8

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