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Investigational New Drugs

, Volume 36, Issue 1, pp 96–102 | Cite as

Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma

  • Glen J. WeissEmail author
  • Lisa Blaydorn
  • Julia Beck
  • Kirsten Bornemann-Kolatzki
  • Howard Urnovitz
  • Ekkhard Schütz
  • Vivek Khemka
PHASE II STUDIES

Summary

Background A single center phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab (GNP) to evaluate the safety and efficacy in metastatic pancreatic adenocarcinoma (PDAC) was conducted (NCT02331251). Methods PDAC patients (pts) with measurable disease, biopsy proven metastasis, adequate laboratory tests, and KPS ≥ 70% received GNP until progression or toxicity. Safety monitoring, RECIST 1.1, and irRECIST assessments were conducted. Response imaging was performed prior to cycle 4, then every 3 months. Changes in tumor cell-free DNA copy number instability (CNI) was retrospectively evaluated. Results 17 pts. with a median age of 56 were treated. 11 were women and all had a KPS of at least 80%. Grade 3 events occurred in 53% of patients. The phase II portion was completed for chemotherapy naïve PDAC pts. Of the 11 evaluable chemotherapy naïve PDAC, the disease control rate (partial response [PR] + stable disease[SD]) was 100%. There were 3 with PR on treatment for 8+, ~11, and 15 months; respectively. The primary endpoint of >15% complete response was not met. The median progression-free survival (PFS) and overall survival (OS) was 9.1 and 15.0 months for chemotherapy naïve treated patients. Of 9 patients evaluable for CNI change, a greater reduction in CNI correlated with longer PFS and improved OS. Conclusions GNP can be safely given to chemotherapy naïve PDAC patients. Efficacy appears to be slightly improved over previously reported results for standard weekly × 3 every 28 day gemcitabine and nab-paclitaxel dosing. CNI change may be prognostic for OS.

Keywords

Pancreatic ductal adenocarcinoma Clinical trial Phase Ib/II Metastatic Chemotherapy Immunotherapy Copy number instability 

Abbreviations

AEs

Adverse events

CNI

Tumor cell-free DNA copy number instability

CI

Confidence interval

DC

Disease control

DLT

Dose-limiting toxicity

irAEs

Immune-related adverse events

irRECIST

Immune-related response criteria

GNP

Gemcitabine and nab-paclitaxel

MTD

Maximum tolerated dose

NSCLC

Non-small cell lung cancer

OS

Overall survival

PD

Disease progression

PDAC

Pancreatic adenocarcinoma

PD-1

Programmed cell death protein 1

PD-L1

PD-1 ligand

PFS

Progression-free survival

RP2D

Recommended phase 2 dose

SD

Stable disease

TEAE

Treatment-emergent AE

WIRB

Western Institutional Review Board

Introduction

Pancreatic adenocarcinoma (PDAC) is a recalcitrant cancer with the majority of patients diagnosed with locally advanced or metastatic disease. This leaves systemic therapy as the main treatment option and overall prognosis is poor with a 5-year survival rate of less than 10% [1]. Since the late 1990’s, gemcitabine has been available as the standard of care regimen in the United States for advanced PDAC [2]. Since 2010, two new combination therapies have been more widely adapted as the standard of care systemic therapy for advanced PDAC, FOLFIRINOX [3] and gemcitabine with nab-paclitaxel [4].

Over the last few years, checkpoint inhibitor therapies targeting programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) have received Federal Drug Administration approval across a number of cancer indications. It is thought that for low immunogenic or stroma fibrotic tumors, that combination therapy may lead to synergistic responses, when the activity of single agent checkpoint inhibition is minimal to lacking. Pembrolizumab, one of the checkpoint inhibitors, in combination with cytoxic chemotherapy was approved in 2017 for use in first-line advanced non-small cell lung cancer (NSCLC) based on data from the phase 2 KEYNOTE-021 study [5].

We previously reported the safety and recommended phase 2 dose (RP2D) of pembrolizumab in combination with several chemotherapy regimens including gemcitabine and nab-paclitaxel (GNP) [6]. Here we report the final results of the phase Ib/II trial of GNP in metastatic PDAC.

Patients and methods

Study design

The phase Ib/II, open-label trial included six separate treatment arms for adults with solid tumors. Here we are reporting the final results from Arm 3, evaluating GNP in metastatic PDAC treated at a single center in the United States. Enrollment was between December 22, 2014 and January 3, 2017. Each patient signed written informed consent prior to initiating any protocol-related activities. The study conformed to Good Clinical Practice guidelines, was reviewed and approved by the Western Institutional Review Board (WIRB), was registered on clinicaltrials.gov (NCT02331251), and was conducted in accordance with the ethical principles set forth in the Declaration of Helsinki.

To be eligible, patients were required to have measurable disease, biopsy proven metastasis, adequate laboratory tests, and Karnofsky Performance Status ≥70% [6]. Patients remained on study until disease progression, refusal, withdrawal of consent, or occurrence of unacceptable toxicity.

Study endpoints

The primary objective of the phase Ib portion was to determine the RP2D of GNP, while complete response by immune-related response criteria (irRECIST) was the primary objective of the phase II portion [7]. Secondary objectives included determining (i) the frequency of grade 3 or higher treatment-related adverse events, (ii) the response rate by irRECIST and response evaluation criteria in solid tumors (RECIST) 1.1 criteria [8], (iii) the overall survival (OS) and progression-free survival (PFS) for enrolled PDAC patients, and (iv) characterization of tumor cell-free DNA copy number instability (CNI) [9].

Assignment of study participants to treatment and dose de-escalation

The dose de-escalation scheme [6] was initiated whereby standard doses for gemcitabine and nab-paclitaxel were based or modified to conform with an every 21 day dosing cycle to coincide with standard pembrolizumab dosing at the time of study launch. Therefore, day 15 gemcitabine and nab-paclitaxel dosing was omitted. For chemotherapy naïve patients, the RP2D was pembrolizumab 2 mg/kg administered intravenously over 30 min every 21 days and infused prior to the start of chemotherapy, and gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on day 1 and day 8 every 21 days [6]. For previously treated PDAC patients, the maximum tolerated dose (MTD) was exceeded, and dosing for gemcitabine and nab-paclitaxel were reduced to 800 mg/m2 and nab-paclitaxel 100 mg/m2 on day 1 and day 8 every 21 days; respectively. This cohort was closed to accrual for futility and a RP2D for previously treated PDAC patients could not be recommended.

Toxicity was graded according to the NCI CTCAE version 4.03. A dose-limiting toxicity (DLT) was defined as any event for which the relationship to study treatment could not be definitely excluded that was observed to occur within the first 21 days of treatment (end of cycle 1) and included: any grade ≥ 3 non-hematologic toxicity (with the exception of self-limiting or medically controllable toxicities lasting <3 days), febrile neutropenia not related to underlying disease, prolonged grade 4 neutropenia (> 7 days), ≥ grade 3 neutropenic infection, ≥ grade 3 thrombocytopenia with bleeding or grade 4 lasting ≥7 days, or missing ≥25% of planned doses over 21 days due to treatment-related adverse events (AEs) in the first cycle [6].

Treatment

No more than two intra-patient dose de-escalations were allowed. In September 2015, the protocol was amended to require dexamethasone 12 mg intravenous premedication on the days of systemic chemotherapy administration in order to minimize the incidence nausea, vomiting, rash, and edema in the extremities. Recommended dose modifications for toxicity were previously detailed [6].

Efficacy assessments

Treatment decisions by the investigator were based on objective tumor assessments performed according to RECIST 1.1 [8] and irRECIST [7]. If a clinically stable patient that met criteria for disease progression (PD) on RECIST 1.1, the investigator could continue treatment on protocol if there was stable disease (SD) or better by irRECIST until there was clinical deterioration, significant toxicity, or PD by irRECIST.

Safety assessments

The highest severity grade attained was reported according to NCI CTCAE version 4.03 and causality between the AE and study treatment was classified as definitely not related, unlikely related, likely related, or definitely related.

CNI characterization

Subjects concurrently participating in protocol no. 20140257 approved by WIRB [9] had their samples analyzed retrospectively. Since all patients with available sample for CNI analysis but one patient (3–011) had SD or better (disease control [DC]) as best response, the evaluation was focused on strength of CNI change at cycle 2 and/or cycle 3 versus the pre-therapeutic baseline values as reported previously [9] and correlated with irRECIST tumor burden at baseline and change at first response scan, PFS on study, and OS. Moderate and strong correlations were defined as having a Pearson’s r coefficient between 0.4–0.7 and >0.7; respectively. To be included in OS Pearson coefficient correlation calculations, a patient had to be deceased or have an OS exceed the mean of 9.67 months. To be included in the PFS Pearson coefficient correlation calculations, a patient had to be off study therapy or have a PFS on study exceed the mean of 6.75 months.

Statistical and analytical plans

All treated patients that completed the first cycle of treatment or had a DLT, were evaluable for the primary endpoints and displayed in the study outputs. Patients that did not complete the first cycle for any reason other than a DLT, were replaced per protocol. Microsoft Excel™ was used for statistical calculations. Pearson correlation coefficients were calculated for comparisons between CNI, irRECIST, PFS on study, and OS. Kaplan-Meier curves were generated for time on therapy and OS using GraphPad Prism version 7.0c (La Jolla, CA).

Results

A total of 19 patients were consented and 17 patients were enrolled, dosed on GNP, and were evaluable for DLT. Two patients were determined to be screen failures and not included in subsequent analyses. At the time of data-cutoff on June 15, 2017, all but three patients were off study treatment.

The median age at study entry was 56 years and 11 were women (Tables 1 and 2). All patients had histologically confirmed metastatic PDAC and had a Karnofsky Performance Status of 80% or better at the time of enrollment. Seven of the 17 patients had prior treatment for PDAC (systemic therapy, surgery, and/or radiation therapy). The number of treatment cycles per patient per treatment arm is provided in Supplementary Table S1.
Table 1

Demographic, baseline, and other patient characteristics

Variable

Treated patients (N = 19)

n

%

Demographic characteristics

 Age (years)

  Median (range)

55 (46–66)

 Sex

  Male

6

35.3

  Female

11

64.7

 KPS Performance status

  100

1

5.9

  90

5

29.4

  80

11

64.7

Prior Anticancer Therapies (Type and Setting)

 Number of Prior Systemic Therapies

  0

12

70.6

  1

5

29.4

 Type of Prior Therapies (n = 7)

  Systemic only

4

57.1

  Surgery only

2

28.6

  Systemic + Radiotherapy

1

14.3

Table 2

Detailed patient demographics with response, duration, and overall survival

Study number

Age at entry

Gender

Prior tx for mets disease

KPS at start

Tumor burden at baseline

△Tumor burden at response scan 1

CNI baseline; max △ CNI at C2/3

Time on Tx (months)

Best response

Survival status

Overall Survival (months)

3–0001

63

M

SX

80%

12.0

−0.9

16; NE

9.1

SD

Deceased

10.3

3–0002

47

F

1 line CT

90%

12.2

−0.1

N/A

5.0

SD

Deceased

14.1

3–0003

55

F

1 line CT

80%

12.4

1.1

N/A

4.9

SD

Deceased

8.0

3–0004

55

F

None

80%

14.0

−4.0

1918; 5

15.3

PR

Deceased

22.6

3–0005

57

M

1 line CT

80%

N/A

N/A

N/A

0.9

NE

Deceased

3.3

3–0007

62

M

SX

90%

18.1

−7.2

5111; −249

10.8

PR

Deceased

15.0

3–0008

63

F

None

100%

9.0

1.7

356; −76

4.4

SD

Alive

17.8

3–0009

57

F

None

80%

10.4

−0.5

2218; −14

4.9

SD

Deceased

6.7

3–0010

61

F

None

80%

17.2

−0.9

6726; −56

4.9

SD

Deceased

7.1

3–0011

52

F

1 line CT, XRT

80%

4.6

8.7

3646; 2450

2.0

PD

Deceased

2.9

3–0012

66

F

None

90%

6.1

−0.4

N/A

5.0

SD

Alive

13.7

3–0013

46

F

1 line CT

80%

9.0

0.9

N/A

2.1

PD

Deceased

4.1

3–0014

65

M

None

90%

5.8

0.0

N/A

7.9

SD

Alive

12.4

3–0015

53

F

None

80%

21.7

NE

126; 231

2.6

NE

Deceased

3.1

3–0016

52

F

None

80%

7.4

−2.4

9; NE

8.2

PR

Alive

8.2

3–0018

55

M

None

80%

5.7

3.5

87; −21

5.4

SD*

Alive

5.4

3–0019

56

M

None

90%

10.9

−0.4

1202; −1186

5.4

SD*

Alive

5.4

M male, F female, CT chemotherapy, XRT radiotherapy, SX surgery, KPS Karnofsky Performance Status, △ change in, PD disease progression, SD stable disease, PR partial response, N/A not available, NE not evaluable, Tx treatment

*pseudo-tumor progression

Dose escalation and first cycle DLTs

The GNP treatment arm initially enrolled chemotherapy treatment naïve and previously treated PDAC patients. After two DLTs in previously treated PDAC patients (grade 3 thrombocytopenia) observed in the first five patients, the protocol was amended splitting this arm into chemotherapy naïve PDAC and previously treated PDAC. For chemotherapy naïve PDAC (Arm 3a), the RP2D is gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1 and 8 every 21 days with P on day 1. As previously reported, the MTD was exceeded for previously treated PDAC and the cohort (Arm 3b) was closed to accrual for futility [6].

Safety results

All (100%) receiving study treatment experienced at least one treatment-emergent AE (TEAE), with 12 patients (70.6%) experiencing TEAEs of Grade 3–4 (Table 3). Once dexamethasone premedication was introduced to all subsequent patients, the incidence of rash decreased. Frequency of immune-related adverse events (irAEs) (likely or definitely-related) was 47.1%. TEAEs at the patient level is detailed in Supplementary Table S1.
Table 3

Treatment emergent adverse events (≥ 20% all grades, ≥ 10% for grades 3–4)

Preferred Term

CTC Grade

Arm 3a

Arm 3b

(N = 15)

(N = 2)

n

%

n

%

Any Term

1–4

9

100

2

100

3–4

11

73.3

1

50

Thrombocytopenia

1–4

6

40

1

50

3–4

3

20

  

Neutropenia

1–4

8

53.3

  

3–4

7

46.7

  

Anemia NOS

1–4

13

86.7

1

50

3–4

    

AST elevation

1–4

7

46.7

  

3–4

1

6.7

  

ALT elevation

1–4

6

40

  

3–4

1

6.7

  

Fatigue

1–4

7

46.7

  

3–4

    

Hyponatremia

1–4

4

26.7

  

3–4

2

13.3

  

White blood cell count decreased

1–4

5

33.3

  

3–4

    

Thrombolic event

1–4

4

26.7

  

3–4

    

ALK increased

1–4

4

26.7

2

100

3–4

  

1

50

Diarrhea

1–4

6

40

  

3–4

    

Peripheral sensory neuropathy

1–4

8

53.3

  

3–4

    

Edema in limbs

1–4

5

33.3

  

3–4

    

Pneumonitis

1–4

3

20

  

3–4

    

Nausea

1–2

3

20

1

50

Vomiting

1–2

4

26.7

1

50

Rash NOS

1–2

4

26.7

1

50

Constipation

1–2

  

1

50

Pain in extremities

1–2

5

33.3

1

50

Mucositis oral

1–2

3

20

  

Hypoalbuminemia

1–2

6

40

  

Dehydration

1–2

3

20

  

Fever

1–2

7

46.7

  

Insomnia

1–2

4

26.7

  

Cough

1–2

3

20

1

50

Rectal and vaginal hemorrhage

1–2

  

1

50

Hot flashes

1–2

3

20

  

Chills

1–2

3

20

  

Abdominal pain

1–2

  

1

50

Hypokalemia

1–2

4

26.7

  

NOS not otherwise specified, AST aspartate aminotransferase, ALT alanine aminotransferase, ALK alkaline phosphatase

After mandatory premedication with dexamethasone was initiated (see Supplementary Table S1), the frequency of grade 3/4 events appears to have decreased. The average number of grade 3/4 events per patient that enrolled prior to this amendment was 2.2 vs 1.1 grade 3/4 events/per patient; respectively. The incidence of likely or definitely-related irAEs for patients was also higher prior to the amendment at 6/6 (100%) compared with 2/11 (18.2%).

One patient died during the study (ie, within 28 days of completion of treatment) due to an intracranial bleed due to surreptitious self-administration of non-steroidal anti-inflammatory drugs, but this death was deemed not to be related to the study medication.

Pharmacodynamic results

Of the 11 patients with serial CNI measurements, 9 had values above the threshold for healthy controls (CNI > 25) [9]. There was a moderate negative correlation between reduction in tumor burden by irRECIST and maximum CNI change after cycle 1 and cycle 2 (r = 0.676). For OS and PFS, 7 and 5 patients could be included, respectively, based on statistical censoring requirements. There was a moderate negative correlation between maximal CNI change and OS (r = −0.534), as well as, reduction in tumor burden by irRECIST and OS (r = −0.605). There was a strong positive correlation between PFS and OS (r = 0.777). There was a strong and moderate negative correlation between reduction in tumor burden by irRECIST and PFS (r = −0.777) and between maximal CNI change and PFS (r = −0.462), respectively.

Efficacy results

15 patients (88%) treated on the study were evaluable for efficacy. On Arm 3a, the best response was partial response (PR) for three patients and SD for eight patients. For previously treated PDAC patients, two had SD at dosing exceeding the MTD, and on Arm 3b, the best response was PD (n = 2). Representative images of a PR, PD, and pseudo-tumor progression responders are displayed in Supplementary Figs. S13. For chemotherapy naïve PDAC (n = 12), the median PFS and OS were 9.1 and 15.0 months, respectively (Figs. 1 and 2).
Fig. 1

PFS for chemotherapy treatment naïve PDAC (n = 12). The solid line shows PFS. The hashed line shows the 95% CI (confidence interval) for the curve

Fig. 2

OS for chemotherapy treatment naïve PDAC (n = 12). The solid line shows OS. The hashed line shows the 95% CI for the curve

Discussion

PDAC is a challenging cancer to treat, with symptoms typically manifesting in later stages of disease. Approximately 43,000 Americans with PDAC die each year and survival is extremely poor with fewer than 10% surviving more than five years [1].

Single agent activity of checkpoint inhibitors has seen the most success in tumor types with high PD-L1 expression and/or high microsatellite instability or mismatch repair deficiency, though this is limited to a population of no more 1/3 of cancer patients for which checkpoint inhibitors are approved [10, 11]. For the general population with advanced PDAC, these agents have minimal single agent activity [12], and the role of combination therapy is being explored across a number of trials. Strategies employed to help select those most likely to benefit from single agent checkpoint inhibition do not appear to play much of a role when combination therapy is contemplated [13, 14, 15].

The present phase Ib/II study is one of the first to report on safety and efficacy of systemic chemotherapy in combination with PD-1 inhibitor in metastatic PDAC. Gemcitabine and paclitaxel have been previously reported to have immunomodulatory properties [16, 17]. Overall, 12 patients with metastatic PDAC were evaluable for the phase II primary endpoint. Based on the design and intent to get a strong signal of efficacy in a small number of patients, it did not meet its goal of three complete responses by irRECIST criteria. The most common toxicities observed regardless of grade were cytopenias, transaminitis, rash, diarrhea, fever, fatigue, nausea, and vomiting. We note a decrease in rash and severity of AEs once once dexamethasone premedication was administered on the days of systemic chemotherapy infusion.

We have recently reported that CNI can be predictive of response to immunotherapy in patients with advance cancer [9]. In patients with available plasma samples, we found in this PDAC cohort that maximal CNI change (after one or two cycles) has moderate negative correlations with reduction in tumor burden by irRECIST, PFS, and OS. In other words, the more CNI decreases, the greater the tumor burden reduction, PFS, and OS. Likewise, we observed negative correlations with reduction in tumor burden by irRECIST, OS, and PFS. Not surprisingly a strong correlation between PFS and OS was found. The limitations of these analyses is small sample size and not all participants had plasma available for CNI analysis (n = 6) or baseline CNI above the level of healthy controls (n = 2); nevertheless, the results are in line with earlier published data using this form of liquid biopsy [9].

Of 11 evaluable chemotherapy naïve PDAC patients for efficacy analysis, there were three with PR and eight with SD as best response (including two with pseudo-tumor progression), for a DC rate of 100%. For chemotherapy naïve PDAC patients (n = 12), the median PFS and OS compare favorably with other treatment regimens that have been built on the gemicitabine and nab-paclitaxel backbone. A recent phase I/II reported results adding cisplatin chemotherapy to the gemcitabine and nab-paclitaxel regimen in 24 evaluable PDAC patients. In this study, the median OS was 16.5 months, a response rate of 71% (17 of 24 evaluable), including 2 complete responses [18]. Other groups are exploring chemotherapy and immunotherapy combinations or immunotherapy only combinations [19, 20], and the final results are eagerly anticipated. With other dosing schedules of immunotherapy and biweekly gemcitabine and nab-paclitaxel appearing to be more tolerable [21], optimal drug delivery to improve efficacy and reduce toxicity may not be determined for quite some time.

In conclusion, this study may help better define the combinations of treatment that may yield impressive and durable results in metastatic PDAC.

Notes

Acknowledgements

The authors express their gratitude and appreciation to all those that participated.

Author contributions

Conception and design: G. Weiss, V. Khemka

Acquisition of data: All authors

Analysis and interpretation of data: All authors

Writing, review, and/or revision of the manuscript: All authors

Administrative, technical, or material support (eg, reporting or organizing data, constructing databases): All authors

Study supervision: G. Weiss, V. Khemka

Funding

This study was funded by Western Regional Medical Center, Inc.

Compliance with ethical standards

Conflict of interest

G. Weiss has been a paid consultant for Blend Therapeutics, Pharmatech, IDEA Pharma, AZ Medical Board, GLG Council, Ignyta, Circulogene Theranostics, Viomics, and Paradigm, has received speaker honorarium from Medscape, Merck, Novartis, and Pfizer; holds ownership interest in Circulogene Theranostics, and travel/accommodations from NantWorks, Cambridge Healthtech Institute, and Tesaro. J. Beck, K. Bornemann-Kolatzki, H. Urnovitz, and E. Schütz are employees of and hold ownership interest in Chronix Biomedical. V. Khemka has been a paid consultant for Axcess Oncology. No potential conflicts of interest were disclosed by the other authors.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10637_2017_525_MOESM1_ESM.docx (28 kb)
ESM 1 (DOCX 28 kb)
10637_2017_525_MOESM2_ESM.pdf (537 kb)
ESM 2 (PDF 536 kb)

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Glen J. Weiss
    • 1
    • 3
    Email author
  • Lisa Blaydorn
    • 1
  • Julia Beck
    • 2
  • Kirsten Bornemann-Kolatzki
    • 2
  • Howard Urnovitz
    • 2
  • Ekkhard Schütz
    • 2
  • Vivek Khemka
    • 1
    • 4
  1. 1.Western Regional Medical Center, Cancer Treatment Centers of AmericaGoodyearUSA
  2. 2.Chronix BiomedicalGöttingenGermany
  3. 3.University of Arizona College of Medicine-PhoenixPhoenixUSA
  4. 4.Virginia G. Piper Cancer CenterScottsdaleUSA

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