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

• ClinicalTrials.gov Identifier: NCT03214250
• Recruitment Status: Completed
• First Posted: July 11, 2017
• Results First Posted: August 11, 2022
• Last Update Posted: December 23, 2022
• Sponsor: Parker Institute for Cancer Immunotherapy
• Collaborators: Bristol-Myers Squibb; Apexigen America, Inc.; Cancer Research Institute, New York City
• Information provided by (Responsible Party): Parker Institute for Cancer Immunotherapy

Tracking Information

• First Submitted Date: June 9, 2017
• First Posted Date: July 11, 2017
• Results First Submitted Date: March 25, 2022
• Results First Posted Date: August 11, 2022
• Last Update Posted Date: December 23, 2022
• Actual Study Start Date: July 21, 2017
• Actual Primary Completion Date: February 11, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 11, 2022)

• Phase 1b Primary Safety Outcome [ Time Frame: 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. ]
  Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)
• 1-year Overall Survival Rate [ Time Frame: 1 year from initiation of study therapy ]
  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.

Original Primary Outcome Measures (submitted: July 10, 2017)

• Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs) [ Time Frame: up to 6 month ]
  Phase 1b Primary Safety Outcome
• Overall survival (OS) defined as the time from initiation of study therapy to date of death due to any cause or date of most recent subject contact. [ Time Frame: up to 5 years ]
  Phase 2 Primary Efficacy Outcome

Current Secondary Outcome Measures (submitted: July 11, 2022)

• Objective Response Rate (ORR): DLT-Evaluable Population [ Time Frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 34.3 months. ]
  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.
• Duration of Response (DOR): DLT-Evaluable Population [ Time Frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 34.3 months. ]
  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.
• Disease Control Rate (DCR) [ Time Frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months. ]
  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.
• Progression-free Survival (PFS) [ Time Frame: Initiation of study drug through radiographic progression or death with a maximum exposure of 24.2 months. ]
  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.
• Objective Response Rate (ORR): Efficacy Population [ Time Frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months. ]
  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.
• Duration of Response (DOR): Efficacy Population [ Time Frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months. ]
  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.

Original Secondary Outcome Measures (submitted: July 10, 2017)

• Objective response rate (ORR) as determined by RECIST criteria [ Time Frame: up to 6 month ]
  Phase 1b and Phase 2 Secondary Efficacy Outcome
• Duration of response (DOR) defined as time from first documentation of response (complete response [CR] or partial response [PR]) to first documentation of progressive disease [ Time Frame: up to 6 month ]
  Phase 1b and Phase 2 Secondary Efficacy Outcome
• Disease control rate (DCR) is defined as the proportion of subjects who achieve a CR or PR or SD [ Time Frame: up to 6 month ]
  Phase 2 Secondary Efficacy Outcome
• Progression free survival (PFS) defined as the time from initiation of study therapy to date of first documented progression of disease, date of death due to any cause or date of most recent subject contact which documented progression free status [ Time Frame: up to 6 month ]
  Phase 2 Secondary Efficacy Outcome

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of APX005M With Gemcitabine and Nab-Paclitaxel With or Without Nivolumab in Patients With Previously Untreated Metastatic Pancreatic Adenocarcinoma
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Pancreatic Adenocarcinoma

Intervention

• Drug: APX005M
  Administer intravenously once every 28-day Cycle
• Drug: Nivolumab
  Administer intravenously twice every 28-day cycle
  Other Name: Opdivo
• Drug: Nab-Paclitaxel
  Administer intravenously on 3 times every 28-day cycle
  Other Name: Abraxane
• Drug: Gemcitabine
  Administer intravenously 3 times every 28-day cycle
  Other Name: Gemzar

Study Arms

• Experimental: Gem/NP/nivolumab
  Gemcitabine+Nab-Paclitaxel+nivolumab
  Interventions:

  • Drug: Nivolumab
  • Drug: Nab-Paclitaxel
  • Drug: Gemcitabine
• Experimental: Gem/NP/APX005M
  Gemcitabine+Nab-Paclitaxel+APX005M
  Interventions:

  • Drug: APX005M
  • Drug: Nab-Paclitaxel
  • Drug: Gemcitabine
• Experimental: Gem/NP/nivolumab/APX005M
  Gemcitabine+Nab-Paclitaxel+nivolumab+APX005M
  Interventions:

  • Drug: APX005M
  • Drug: Nivolumab
  • Drug: Nab-Paclitaxel
  • Drug: Gemcitabine

Publications *

• 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.
• 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.
• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22;12(4):252-64. doi: 10.1038/nrc3239.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 12, 2019): 129
• Original Estimated Enrollment (submitted: July 10, 2017): 105
• Actual Study Completion Date: February 25, 2022
• Actual Primary Completion Date: February 11, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03214250
• Other Study ID Numbers: PICI0002; UPCC 11217 ( Other Identifier: University of Pennsylvania )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Parker Institute for Cancer Immunotherapy
• Original Responsible Party: Same as current
• Current Study Sponsor: Parker Institute for Cancer Immunotherapy
• Original Study Sponsor: Same as current

Collaborators

• Bristol-Myers Squibb
• Apexigen America, Inc.
• Cancer Research Institute, New York City

Investigators

• Study Director: Parker Institute for Cancer Immunotherapy; Parker Institute for Cancer Immunotherapy

• PRS Account: Parker Institute for Cancer Immunotherapy
• Verification Date: December 2022