Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with Nab-Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Phase I Results.

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. © AlphaMed Press; the data published online to support this summary is the property of the authors.

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

Pancreatic cancer

Metastatic/advanced

None

Phase I

3 + 3

Safety

Tolerability

MTD

Recommended phase II dose

PK

PD

Activity and safety demonstrated. Proceeded to randomized phase II, but futility met in phase II

Drug Information for Phase I Control

Necuparanib

Momenta Pharmaceuticals

Biological

Other: heparan sulfate mimetic

0.5–5 milligrams (mg) per kilogram (kg)

Other: subcutaneous

Daily subcutaneous doses in cohorts from 0.5 to 5 mg/kg; dose capped at 450 mg

Nab‐paclitaxel

Abraxane

Celgene

Small molecule

Tubulin/Microtubules targeting agent

125 mg/m2

IV

Days 1, 8, and 15 of a 28‐day cycle

Gemcitabine

Gemzar

Eli Lilly

Small molecule

Antimetabolite

1,000 mg/m2

IV

Days 1, 8, and 15 of a 28‐day cycle

New drug

Momenta Pharmaceuticals

Biological

Other

0.5 mg/kg

Subcutaneous

Patient Characteristics for Phase I Control

12

27

IV pancreas adenocarcinoma

Median (range): 63 years

Median (range): 0

0 — 21

1 — 18

2 —

3 —

Unknown —

Primary Assessment Method for Phase I Control

Necuparanib, nab‐paclitaxel, gemcitabine (n = 24)

39

39

24

RECIST 1.1

n = 0 (0%)

n = 9 (38%)

n = 6 (25%)

n = 2 (8%)

5.9 months, CI: 2.1–8.7

13.1 months, CI: 4.0–16.6

Phase I Control Adverse Events

Dose‐Limiting Toxicities Table

Assessment, Analysis, and Discussion

Study completed

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.

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.

Concentration of necuparanib for patients with at least three measurable levels on day 1.

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.

Mean (standard deviation) serum hepatocyte growth factor levels by dose group

Abbreviations: Gem, gemcitabine; HGF, hepatocyte growth factor; NabP, nab‐paclitaxel; necu, necuparanib.

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.

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.

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.

Abbreviations: aPTT, activated partial thromboplastin time; LFT, liver function test.

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.