Safety and Efficacy of APX005M With Gemcitabine and Nab-Paclitaxel With or Without Nivolumab in Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma

Open-label, Multicenter, Phase 1b/2 Clinical Study to Evaluate the Safety and Efficacy of CD40 Agonistic Monoclonal Antibody (APX005M) Administered Together With Gemcitabine and Nab-Paclitaxel With or Without PD-1 Blocking Antibody (Nivolumab) in Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma

The main purposes of this study are to learn how effective the study drug combinations are in treating patients with metastatic pancreatic adenocarcinoma. The drug combinations are APX005M+Nivolumab+Gemcitabine+nab-Paclitaxel, or APX005M+Gemcitabine+nab-Paclitaxel.

Study Overview

• Status: Completed
• Conditions: Metastatic Pancreatic Adenocarcinoma
• Intervention / Treatment: Drug: Nivolumab; Drug: Nab-Paclitaxel; Drug: Gemcitabine; Drug: APX005M

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
    • Stanford, California, United States, 94305
      • Stanford University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania, Abramson Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject has histologically or cytologically documented diagnosis of pancreatic adenocarcinoma with metastatic disease. Locally advanced subjects are not eligible.
2. Subject must have measureable disease by RECIST 1.1.
3. Subjects must be age 18 years or older.
4. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

5. Subjects must have the following laboratory values at screening within 2 weeks of the first dose of investigational agents:

   • Absolute neutrophil count (ANC) ≥1.5 x 109/L (in absence of growth factor support)
   • Platelet count ≥150 x 109/L
   • Hemoglobin ≥9 g/dL(without transfusion support)
   • Serum creatinine ≤1.5 mg/dL, and creatinine clearance ≥ 50 ml/min as measured by Cockcroft and Gault formula
   • Aspartate aminotransferase (AST) and ALT ≤2.5 x upper limit of normal (ULN)
   • Total bilirubin ≤1.5 x ULN, except in subjects with documented Gilbert's Syndrome, who must have a total bilirubin ≤3 x ULN
6. Women of childbearing potential (WOCBP) must have a negative pregnancy test (serum or urine) within the 7 days prior to study drug administration, and within the 3 days before the first study drug administration, or a negative pregnancy test within the 24 hours before the first study drug administration.
7. WOCBP and male subjects who are sexually active with WOCBP must agree to use 2 highly effective methods of contraception (including a physical barrier) before the first dose of study drugs, during the study, and for 5 months for women and 7 months for men following the last dose of study drug.
8. Subjects must have the ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. Subject must not have received any prior treatment, including chemotherapy, biological therapy, or targeted therapy for metastatic pancreatic adenocarcinoma, with the following exceptions and notes:

   1. Subjects who have received prior adjuvant therapy for pancreatic adenocarcinoma are eligible if neoadjuvant and adjuvant therapy (including chemotherapy and/or radiotherapy) was fully completed more than 4 months before the start of study treatment. In this case, prior Gem and/or NP is allowable
   2. Prior resection surgery is allowable.
   3. Patients initially diagnosed with locally advanced pancreatic cancer who have undergone chemotherapy then resection and were with no evidence of disease are eligible if metastatic relapse of disease has occurred and if the last dose of chemotherapy was more than 4 months before the data of study entry.

2. Subjects must not have another active invasive malignancy, with the following exceptions and notes:

   1. History of a non-invasive malignancy, such as cervical cancer in situ, non-melanomatous carcinoma of the skin, in situ melanoma, or ductal carcinoma in situ of the breast, is allowed.
   2. History of malignancy that is in complete remission after treatment with curative intent is allowed.
   3. No current or history of a hematologic malignancy is allowed, including subjects who have undergone a bone marrow transplant.
3. History of clinically significant sensitivity or allergy to monoclonal antibodies, their excipients, or intravenous gamma globulin
4. Previous exposure to CD40, PD-1, PD-L1, CTLA-4 antibodies or any other immunomodulatory agent
5. History of (non-infectious) pneumonitis that required corticosteroids or current pneumonitis, or history of interstitial lung disease

6. Subjects must not have a known or suspected history of an autoimmune disorder, including but not limited to inflammatory bowel disease, celiac disease, Wegner syndrome, Hashimoto syndrome, systemic lupus erythematosus, scleroderma, sarcoidosis, or autoimmune hepatitis, within 3 years of the first dose of investigational agent, except for the following.

   a. Subjects with Type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders such as vitiligo, or alopecia not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger are eligible.

7. Subjects must not have an uncontrolled intercurrent illness, including an ongoing or active infection, current pneumonitis, symptomatic congestive heart failure (New York Heart Association class III or IV), unstable angina, uncontrolled hypertension, cardiac arrhythmia, interstitial lung disease, active coagulopathy, or uncontrolled diabetes.
8. Subjects must not have a history of myocardial infarction within 6 months or a history of arterial thromboembolic event within 3 months of the first dose of investigational agent.

9. Subjects must not have a history of human immunodeficiency virus, hepatitis B, or hepatitis C, except for the following:

   1. subjects with anti-hepatitis B core antibody but with undetectable HBV DNA and negative for HBsAg
   2. subjects with resolved or treated HCV (i.e. HCV antibody positive but undetectable HCV RNA)
10. Subjects must not have a history of primary immunodeficiency.

11. Subjects must not receive concurrent or prior use of an immunosuppressive agent within 14 days of the first dose of investigational agent, with the following exceptions and notes:

    1. Systemic steroids at physiologic doses (equivalent to dose of oral prednisone 10 mg) are permitted. Steroids as anti-emetics for chemotherapy are not allowed.
    2. Intranasal, inhaled, topical, intra-articular, and ocular corticosteroids with minimal systemic absorption are permitted.
    3. Subjects with a condition with anticipated use of systemic steroids above the equivalent of 10 mg prednisone are excluded.

12. Subjects must not have a history of clinically manifested central nervous system (CNS) metastases.

    a. Subjects with known or suspected leptomeningeal disease or cord compression are not eligible.

13. Subjects must not have had major surgery as determined by the PI within 4 weeks before the first dose of investigational agent.
14. Subjects must not have received another investigational agent within the shorter of 4 weeks or 5 half-lives before the first dose of investigational agent.
15. Subjects must not have received a live attenuated vaccine within 28 days before the first dose of investigational agent, and subjects, if enrolled, should not receive live vaccines during the study or for 180 days after the last dose of investigational agent.
16. Females who are pregnant or lactating or who intend to become pregnant during participation in the study are not eligible to participate.
17. Subjects who are of reproductive potential who refuse to use effective methods of birth control during the course of participation of the study and within 5 month for women and 7 months for men of the last dose of investigational agent are ineligible to participate in the study.
18. Subjects who have any clinically significant psychiatric, social, or medical condition that, in the opinion of the investigator, could increase the subject's risk, interfere with protocol adherence, or affect the subject's ability to give informed consent are ineligible to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Gem/NP/nivolumab; Gemcitabine+Nab-Paclitaxel+nivolumab	Drug: Nivolumab; Administer intravenously twice every 28-day cycle; Other Names: Opdivo; Drug: Nab-Paclitaxel; Administer intravenously on 3 times every 28-day cycle; Other Names: Abraxane; Drug: Gemcitabine; Administer intravenously 3 times every 28-day cycle; Other Names: Gemzar
Experimental: Gem/NP/APX005M; Gemcitabine+Nab-Paclitaxel+APX005M	Drug: Nab-Paclitaxel; Administer intravenously on 3 times every 28-day cycle; Other Names: Abraxane; Drug: Gemcitabine; Administer intravenously 3 times every 28-day cycle; Other Names: Gemzar; Drug: APX005M; Administer intravenously once every 28-day Cycle
Experimental: Gem/NP/nivolumab/APX005M; Gemcitabine+Nab-Paclitaxel+nivolumab+APX005M	Drug: Nivolumab; Administer intravenously twice every 28-day cycle; Other Names: Opdivo; Drug: Nab-Paclitaxel; Administer intravenously on 3 times every 28-day cycle; Other Names: Abraxane; Drug: Gemcitabine; Administer intravenously 3 times every 28-day cycle; Other Names: Gemzar; Drug: APX005M; Administer intravenously once every 28-day Cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b Primary Safety Outcome	Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)	Initiation of study drug (or informed consent for SAEs) through 100 days after the last dose of study drug or initiation of a new systemic anti-cancer therapy with a maximum exposure of 34.3 months.
1-year Overall Survival Rate	The primary endpoint was the 1-year OS rate of each treatment arm, compared to the historical rate of 35% for gemcitabine and nab-Paclitaxel. OS was defined as the time from treatment initiation until death from any cause. Patients who were not reported as having died at the time of analysis were censored at the most recent contact date. OS and the 1-year OS rate were estimated by the Kaplan-Meier method for each treatment arm. The 1-year OS rate and corresponding one-sided, 95% CI were calculated to determine whether the lower bound of the CI excluded the assumed historical value of 35%. P values were calculated using a one-sided, one-sample z-test of the Kaplan-Meier estimate of the 1-year OS rate (and its standard error) against the historical rate of 35%. This study was not powered for statistical comparison between arms.	1 year from initiation of study therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR): DLT-Evaluable Population	Phase 1b DLT-Evaluable Population. Overall Response Rate is defined as the proportion of participants who had a best overall response of Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1. Overall Response (OR) = CR + PR.	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 34.3 months.
Duration of Response (DOR): DLT-Evaluable Population	DOR was the time from the first tumor assessment demonstrating response until the date of radiographic disease progression. DOR and the CIs were estimated using the Kaplan-Meier method.	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 34.3 months.
Disease Control Rate (DCR)	Phase 2 Secondary Efficacy Outcome. Disease Control Rate is defined as the proportion of participants who had a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) as defined by RECIST v1.1.	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months.
Progression-free Survival (PFS)	PFS is defined as the time from treatment initiation until radiographic disease progression or death (whichever occurred first). PFS and the CIs were estimated using the Kaplan-Meier method.	Initiation of study drug through radiographic progression or death with a maximum exposure of 24.2 months.
Objective Response Rate (ORR): Efficacy Population	Phase 2 Secondary Efficacy Outcome. Overall Response Rate is defined as the proportion of participants who had a best overall response of Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1. Overall Response (OR) = CR + PR.	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months.
Duration of Response (DOR): Efficacy Population	DOR was the time from the first tumor assessment demonstrating response until the date of radiographic disease progression. DOR and the CIs were estimated using the Kaplan-Meier method.	Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months.

Collaborators and Investigators

• Sponsor: Parker Institute for Cancer Immunotherapy
• Collaborators: Bristol-Myers Squibb; Cancer Research Institute, New York City; Apexigen, Inc.

Publications and helpful links

General Publications

• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. doi: 10.1038/nrc3239.
• Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. doi: 10.1056/NEJMoa1200690. Epub 2012 Jun 2.
• Bauer C, Kuhnemuth B, Duewell P, Ormanns S, Gress T, Schnurr M. Prevailing over T cell exhaustion: New developments in the immunotherapy of pancreatic cancer. Cancer Lett. 2016 Oct 10;381(1):259-68. doi: 10.1016/j.canlet.2016.02.057. Epub 2016 Mar 8.
• Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. doi: 10.1056/NEJMoa1304369. Epub 2013 Oct 16.
• Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014 Jun 1;74(11):2913-21. doi: 10.1158/0008-5472.CAN-14-0155. Erratum In: Cancer Res. 2014 Jul 15;74(14):4006.
• Khong A, Nelson DJ, Nowak AK, Lake RA, Robinson BW. The use of agonistic anti-CD40 therapy in treatments for cancer. Int Rev Immunol. 2012 Aug;31(4):246-66. doi: 10.3109/08830185.2012.698338.
• Padron LJ, Maurer DM, O'Hara MH, O'Reilly EM, Wolff RA, Wainberg ZA, Ko AH, Fisher G, Rahma O, Lyman JP, Cabanski CR, Yu JX, Pfeiffer SM, Spasic M, Xu J, Gherardini PF, Karakunnel J, Mick R, Alanio C, Byrne KT, Hollmann TJ, Moore JS, Jones DD, Tognetti M, Chen RO, Yang X, Salvador L, Wherry EJ, Dugan U, O'Donnell-Tormey J, Butterfield LH, Hubbard-Lucey VM, Ibrahim R, Fairchild J, Bucktrout S, LaVallee TM, Vonderheide RH. Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial. Nat Med. 2022 Jun;28(6):1167-1177. doi: 10.1038/s41591-022-01829-9. Epub 2022 Jun 3.
• O'Hara MH, O'Reilly EM, Varadhachary G, Wolff RA, Wainberg ZA, Ko AH, Fisher G, Rahma O, Lyman JP, Cabanski CR, Mick R, Gherardini PF, Kitch LJ, Xu J, Samuel T, Karakunnel J, Fairchild J, Bucktrout S, LaVallee TM, Selinsky C, Till JE, Carpenter EL, Alanio C, Byrne KT, Chen RO, Trifan OC, Dugan U, Horak C, Hubbard-Lucey VM, Wherry EJ, Ibrahim R, Vonderheide RH. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. Lancet Oncol. 2021 Jan;22(1):118-131. doi: 10.1016/S1470-2045(20)30532-5.

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2017
• Primary Completion (Actual): February 11, 2021
• Study Completion (Actual): February 25, 2022

Study Registration Dates

• First Submitted: June 9, 2017
• First Submitted That Met QC Criteria: July 10, 2017
• First Posted (Actual): July 11, 2017

Study Record Updates

• Last Update Posted (Actual): December 23, 2022
• Last Update Submitted That Met QC Criteria: December 21, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Gemcitabine; Nivolumab; nab-Paclitaxel; APX005M; previously untreated metastatic pancreatic adenocarcinoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Gemcitabine; Paclitaxel; Nivolumab
• Other Study ID Numbers: PICI0002; UPCC 11217 (Other Identifier: University of Pennsylvania)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No