Abstract
Lessons Learned.
Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing.
Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low‐level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling.
Background.
Necuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin‐associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabine ± nab‐paclitaxel in patients with metastatic pancreatic cancer.
Methods.
Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m2 gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m2 nab‐paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3 + 3 design until the maximum tolerated dose (MTD) was determined.
Results.
Thirty‐nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg + gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg + nab‐paclitaxel + gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib + nab‐paclitaxel + gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and selected for further assessment in phase II.
Conclusion.
Acceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab‐paclitaxel, and gemcitabine were demonstrated.
Abstract
摘要
背景.Necuparanib是普通肝素的衍生物, 经基因改造为在保留已知肝素相关抗肿瘤特性的同时降低抗凝血活性。本试验评估了necuparanib联合吉西他滨±白蛋白结合型紫杉醇治疗转移性胰腺癌患者的安全性、药代动力学（PK）、药效学和初始疗效。
材料与方法.患者每天接受剂量递增的necuparanib皮下注射+吉西他滨1,000 mg/m2（第1、8和15天, 28天一个周期）。在两个队列后对方案进行了修订, 纳入白蛋白结合型紫杉醇125 mg/m2（发布III期MPACT数据之后）。Necuparanib的起始剂量为0.5mg/kg, 通过修订后的3 + 3设计进行剂量递增, 直至确定最大耐受剂量（MTD）。
结果.39例患者入组进入7个队列（necuparanib 0.5, 1 mg/kg +吉西他滨；necuparanib 1, 2, 4, 6和5 mg/kg +白蛋白结合型紫杉醇+吉西他滨）。最常见的不良事件为贫血（56%）、疲乏（51%）、中性粒细胞减少症（51%）、白细胞减少症（41%）和血小板减少症（41%）。研究期间发生了两起可能与necuparanib有关的严重不良事件, 未发生死亡事件。从2 mg/kg剂量水平开始可检出necuparanib。在至少接受了1次necuparanib+白蛋白结合型紫杉醇+吉西他滨给药的24例患者中, 9例（38%）患者达到部分缓解, 6例（25%）达到疾病稳定（63%疾病控制率）。由于6 mg/kg剂量水平下发生蜂窝织炎事件和活化部分凝血活酶时间轻度延长, 判定5 mg/kg剂量水平为MTD并且将在II期研究中对其进行进一步评估。
结论.研究证实接受necuparanib、白蛋白结合型紫杉醇和吉西他滨治疗的转移性胰腺癌患者的安全性可接受且活性较好。
Discussion
Heparins are present as cell surface glycosaminoglycans and have crucial regulatory roles in normal physiological processes and pathophysiological conditions, including tumor onset, proliferation, and metastasis [1], [2], [3], [4]. Possible antitumor effects of heparin include prevention of metastasis via inhibition of heparanase and interaction with P‐selectin [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. Heparin administration is limited by its anticoagulant effects. Necuparanib is a noncytotoxic, glycol‐split, heparan sulfate mimetic intended to treat advanced malignancies. Necuparanib is rationally engineered from heparin through a process that reduces anticoagulant activity while preserving activity against a number of heparin‐binding proteins involved in tumor progression and metastasis. [15], [16], [17]
This is the first clinical evaluation of necuparanib, a novel therapeutic agent, which was conducted in patients with metastatic pancreatic adenocarcinoma. Necuparanib in combination with nab‐paclitaxel and gemcitabine demonstrated acceptable tolerability. No clear dose‐proportional trends in individual adverse events (AEs) were observed. The most common AEs had comparable rates, when necuparanib was administered with gemcitabine with or without nab‐paclitaxel, to what would be expected with chemotherapy alone. The grade 3/4 hematological toxicities observed in this study in the necuparanib + nab‐paclitaxel and gemcitabine cohort were similar to those observed in the Von Hoff phase III MPACT trial (neutropenia, 3% vs. 38%; anemia, 3% vs. 13%; and thrombocytopenia, 0% vs. 13%, respectively). No grade 3/4 AEs of leukocytosis, febrile neutropenia, epistaxis, pulmonary embolism, deep vein thrombosis, phlebitis, or hematuria were reported with the necuparanib + nab‐paclitaxel and gemcitabine regimen.
Based on collective safety and on PK, progressive disease (PD), biomarker, and efficacy data, a 5 mg/kg necuparanib dose, with capping at 450 mg, providing for a reasonable injection volume (i.e., two injections daily), was selected for further clinical evaluation in part B (randomized phase II trial). Pharmacodynamic data (i.e., hepatocyte growth factor) showed saturation with necuparanib 5 mg/kg and subtherapeutic levels of anticoagulation, which may be beneficial for thrombosis prevention. Promising antitumor activity was observed, as evidenced by survival and response data, with an overall disease‐control rate of 63% when all dose cohorts were pooled. Similarly, promising effects on reduction in Carbohydrate antigen 19‐9 (CA19.9) levels from baseline with necuparanib treatment were observed. The median overall survival for patients who received at least one dose (13.1 months) and at least one cycle (15.6 months) of necuparanib + nab‐paclitaxel + gemcitabine compared favorably with the phase III data for nab‐paclitaxel + gemcitabine (8.5 months), differences in sample sizes and study populations notwithstanding [18].
These encouraging phase I results supported further clinical investigation in part B of this two‐part study; however, the phase II portion of the trial was discontinued following a planned interim futility analysis, which did not show a sufficient level of efficacy to warrant continuation of study accrual. The phase II results will be reported separately.
Trial Information
- Disease
Pancreatic cancer
- Stage of Disease/Treatment
Metastatic/advanced
- Prior Therapy
None
- Type of Study – 1
Phase I
- Type of Study – 2
3 + 3
- Primary Endpoint
Safety
- Primary Endpoint
Tolerability
- Secondary Endpoin
MTD
- Secondary Endpoint
Recommended phase II dose
- Secondary Endpoint
PK
- Secondary Endpoint
PD
- Additional Details of Endpoints or Study Design This was a phase I, open‐label, multiple ascending‐dose study of necuparanib given as monotherapy and then in combination with nab‐paclitaxel and gemcitabine for patients with newly diagnosed untreated metastatic pancreas adenocarcinoma. Following completion of the first two cohorts (0.5 and 1.0 mg/kg necuparanib + gemcitabine), a protocol amendment in 2013 added nab‐paclitaxel to the regimen following the presentation of MPACT study results supporting the combination. Dose escalation was conducted via a modified 3 + 3 design and occurred if all patients in the studied cohort completed cycle 1 without a dose‐limiting toxicity (DLT). If a DLT was observed in one patient in the initial cohort of three to four patients, the cohort was expanded to six or seven patients. Dose escalation continued until the maximum tolerated dose (MTD) was defined. The protocol was modified during cohort 6 dosing to specify a maximum necuparanib dose of 450 mg (maximum of two injections of 225 mg/1.5 mL for each injection) following indications that daily doses greater than this were associated with elevated coagulation parameters. Dose escalation was to be terminated if two patients in the same cohort experienced a DLT in cycle 1. A DLT was defined as any AE judged by the investigator to be drug‐related and assessed as grade ≥3 according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Safety data in patients who received at least one dose of at least one of the study drugs were summarized by treatment group, and descriptive statistics were calculated for quantitative data and differences from baseline, as appropriate. Pharmacokinetic and PD parameters were calculated using noncompartmental methods and summarized by treatment group using descriptive statistics.
- Investigator's Analysis
Activity and safety demonstrated. Proceeded to randomized phase II, but futility met in phase II
Drug Information for Phase I Control
- Drug 1
- Generic/Working name
Necuparanib
- Company name
Momenta Pharmaceuticals
- Drug type
Biological
- Drug class
Other: heparan sulfate mimetic
- Dose
0.5–5 milligrams (mg) per kilogram (kg)
- Route
Other: subcutaneous
- Schedule of administration
Daily subcutaneous doses in cohorts from 0.5 to 5 mg/kg; dose capped at 450 mg
- Drug 2
- Generic/Working name
Nab‐paclitaxel
- Trade name
Abraxane
- Company name
Celgene
- Drug type
Small molecule
- Drug class
Tubulin/Microtubules targeting agent
- Dose
125 mg/m2
- Route
IV
- Schedule of administration
Days 1, 8, and 15 of a 28‐day cycle
- Drug 3
- Generic/Working name
Gemcitabine
- Trade name
Gemzar
- Company name
Eli Lilly
- Drug type
Small molecule
- Drug class
Antimetabolite
- Dose
1,000 mg/m2
- Route
IV
- Schedule of administration
Days 1, 8, and 15 of a 28‐day cycle
- Drug 4
- Generic/Working name
New drug
- Company name
Momenta Pharmaceuticals
- Drug type
Biological
- Drug class
Other
- Dose
0.5 mg/kg
- Route
Subcutaneous
Patient Characteristics for Phase I Control
- Number of Patients, Male
12
- Number of Patients, Female
27
- Stage
IV pancreas adenocarcinoma
- Age
Median (range): 63 years
- Number of Prior Systemic Therapies
Median (range): 0
- Performance Status: ECOG
-
0 — 21
1 — 18
2 —
3 —
Unknown —
Primary Assessment Method for Phase I Control
- Title
Necuparanib, nab‐paclitaxel, gemcitabine (n = 24)
- Number of Patients Enrolled
39
- Number of Patients Evaluable for Toxicity
39
- Number of Patients Evaluated for Efficacy
24
- Evaluation Method
RECIST 1.1
- Response Assessment CR
n = 0 (0%)
- Response Assessment PR
n = 9 (38%)
- Response Assessment SD
n = 6 (25%)
- Response Assessment PD
n = 2 (8%)
- (Median) Duration Assessments PFS
5.9 months, CI: 2.1–8.7
- (Median) Duration Assessments OS
13.1 months, CI: 4.0–16.6
Phase I Control Adverse Events
n (%) patients are shown. Adverse events have been sorted by necuparanib + gemcitabine + nab‐paclitaxel (cohort 3–7 total) results.
Abbreviations: —, no adverse event; ↑, increased; AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Co, cohort.
Dose‐Limiting Toxicities Table
Abbreviations: aPTT, activated partial thromboplastin time; LFT, liver function test.
Assessment, Analysis, and Discussion
- Completion
Study completed
- Investigator's Assessment
Activity and safety demonstrated. Proceeded to randomized phase II, but futility met in phase II
This was the first clinical evaluation of necuparanib, a novel therapeutic agent, which was conducted in patients with metastatic pancreatic adenocarcinoma. Necuparanib in combination with nab‐paclitaxel and gemcitabine demonstrated acceptable tolerability. No clear dose‐proportional trends in individual adverse events (AEs) were observed. The most common AEs had comparable rates, when necuparanib was administered with gemcitabine with or without nab‐paclitaxel, to what would be expected with chemotherapy alone. With the exception of anemia, the grade 3/4 hematological toxicities observed in this study in the necuparanib + nab‐paclitaxel and gemcitabine cohort were similar to those observed in the Von Hoff et al. phase III study (neutropenia, 3% vs. 38%; anemia, 3% vs. 13%; and thrombocytopenia, 0% vs. 13%, respectively). No grade 3/4 AEs of leukocytosis, febrile neutropenia, epistaxis, pulmonary embolism, deep vein thrombosis, phlebitis, or hematuria were reported with the necuparanib + nab‐paclitaxel and gemcitabine regimen.
Based on collective safety and on pharmacokinetic, progressive disease, biomarker, and efficacy data, a 5 mg/kg necuparanib dose, with capping at 450 mg, providing for a reasonable injection volume (i.e., two injections daily), was selected for further clinical evaluation in part B. Progressive disease data (i.e., hepatocyte growth factor) showed saturation with necuparanib 5 mg/kg and subtherapeutic levels of anticoagulation, which may be beneficial for thrombosis prevention. Promising antitumor activity was observed, as evidenced by survival and response data, with an overall disease‐control rate of 63% when all dose cohorts were pooled. Similarly, promising effects on reduction in CA19.9 levels from baseline with necuparanib treatment were observed. The median OS for patients who received at least one dose (13.1 months) and at least one cycle (15.6 months) of necuparanib + nab‐paclitaxel + gemcitabine compared favorably with the phase III data for nab‐paclitaxel + gemcitabine (8.5 months), differences in sample sizes and study populations notwithstanding.
These encouraging phase I results supported further clinical investigation in part B of this two‐part study; however, the phase II portion of the trial was discontinued following a planned interim futility analysis, which did not show a sufficient level of efficacy to warrant continuation of study accrual. The phase II results will be documented in a separate publication.
Figures and Tables
Figure 1.
Dose escalation and disposition in patients receiving at least one dose of necuparanib.
Abbreviations: aPTT, activated partial thromboplastin time; DLT, dose‐limiting toxicity; Gem, gemcitabine; HGF, hepatocyte growth factor; LFTs, liver function tests; NabP, nab‐paclitaxel; Necu, necuparanib; PK, pharmacokinetics.
Figure 2.
Concentration of necuparanib for patients with at least three measurable levels on day 1.
Figure 3.
Activated partial thromboplastin time and prothrombin time in patients who received necuparanib in combination with nab‐paclitaxel and gemcitabine (cohorts 3–7).
Abbreviations: aPTT, activated partial thromboplastin time; PT, prothrombin time.
Figure 4.
Mean (standard deviation) serum hepatocyte growth factor levels by dose group
Abbreviations: Gem, gemcitabine; HGF, hepatocyte growth factor; NabP, nab‐paclitaxel; necu, necuparanib.
Figure 5.
Patient time on study for patients receiving necuparanib + gemcitabine (cohorts 1 and 2; A) or necuparanib + nab‐paclitaxel + gemcitabine (cohorts 3–7; B).
Abbreviations: Gem, gemcitabine; NabP, nab‐paclitaxel; NE, not evaluable; Necu, necuparanib; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 6.
Patient time on study for patients receiving necuparanib + gemcitabine (cohorts 1 and 2; A) or necuparanib + nab‐paclitaxel + gemcitabine (cohorts 3–7; B).
Abbreviations: Gem, gemcitabine; NabP, nab‐paclitaxel; NE, not evaluable; Necu, necuparanib; PD, progressive disease; PR, partial response; SD, stable disease.
Table 1. Baseline patient and disease characteristics.
Data were available for the following numbers of patients (necuparanib + gemcitabine, necuparanib + nab‐paclitaxel + gemcitabine): ECOG (11, 24); tumor location and number of metastatic sites (12, 23); CA19.9 (9, 27).
aNot available for three patients.
Abbreviations: BMI, body mass index; CA, cancer antigen; ECOG, Eastern Cooperative Oncology Group.
Table 2. Summary of adverse events.
n (%) patients are shown. Adverse events have been sorted by necuparanib + gemcitabine + nab‐paclitaxel (cohort 3–7 total) results.
Abbreviations: —, no adverse event; ↑, increased; AE, adverse event; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Co, cohort;
Table 3. Efficacy outcomes.
Abbreviations: CI, confidence interval; CR, complete response; mo, Month; NE, not evaluable; PD, progressive disease; PFS, progression‐free survival; PR, partial response; OS, overall survival; RECIST, Response Evaluation Criteria In Solid Tumors; SD, Stable disease.
Acknowledgments
Research funding support was provided by Momenta Pharmaceuticals.
Footnotes
ClinicalTrials.gov Identifier: NCT01621243
Sponsor(s): Momenta Pharmaceuticals
Principal Investigator: Eileen M. O'Reilly
IRB Approved: Yes
See the related commentary on page 1424.
Disclosures
Eileen M. O'Reilly: Celgene, MedImmune, Halozyme (C/A), Celgene, MabVax, Roche, Momenta Pharmaceuticals, Sanofi, Oncomed, MedImmune, AstraZenica, Bristol‐Meyers Squibb (RF); James Roach: Momenta Pharmaceuticals (E, OI [former]); Molly Rosano: Momenta Pharmaceuticals (E, OI); Silva Krause: Momenta Pharmaceuticals (E, OI); William Avery: Momenta Pharmaceuticals (E); Julie Wolf: Novella Clinical (E); Keith Flaherty: Momenta (C/A); Darrell Nix: Momenta (C/A). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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