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

Conditions

Metastatic Pancreatic Adenocarcinoma

Keywords

Nivolumab, APX005M, previously untreated metastatic pancreatic adenocarcinoma, Gemcitabine, nab-Paclitaxel

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.

Ji Yun Kim, Ning Wang, Benjamin R. Weeder, Enzo Stagnaro, Karim Mrouj et al. (18 authors)

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Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma

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10.1038/s41467-024-49915-5

Clinical benefit of granulocyte-colony stimulating factor (GCSF) use during chemoimmunotherapy treatment for metastatic pancreatic adenocarcinoma (mPDAC).

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Journal of Clinical Oncology2023-01-24

10.1200/jco.2023.41.4_suppl.757

602 Mass spectrometry-based protein biomarker analysis in chemoimmunotherapy combinations identifies unique immune signatures in pancreatic cancer

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10.1136/jitc-2022-sitc2022.0602

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Lacey Padrón, Deena M. Maurer, Mark H. O’Hara, Eileen M. O’Reilly, Robert A. Wolff et al. (37 authors)

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10.1038/s41591-022-01829-9

Circulating <i>KRAS</i> variant-specific shedding and association with survival in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving chemoimmunotherapy.

Jacob E. Till, Lee McDaniel, Shannon M. Pfeiffer, Deena M. Maurer, Jia Xin Yu et al. (20 authors)

Journal of Clinical Oncology2022-06-011 citations

10.1200/jco.2022.40.16_suppl.2548

Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer.

Lacey Padrón, Deena M. Maurer, Mark H. O’Hara, Eileen M. O’Reilly, Robert A. Wolff et al. (20 authors)

Journal of Clinical Oncology2022-06-01

10.1200/jco.2022.40.16_suppl.4010

Feasibility and utility of synthetic control arms derived from real-world data to support clinical development.

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Journal of Clinical Oncology2022-01-194 citations

10.1200/jco.2022.40.4_suppl.528

343 Multiomic biomarker signatures identify subsets of patients who may benefit from either nivolumab or sotigalimab in combination with chemotherapy in metastatic pancreatic cancer

Deena M. Maurer, Jia Xin Yu, Kamil Skłodowski, Marco Tognetti, Lukas Reiter et al. (22 authors)

Regular and Young Investigator Award Abstracts2021-11-011 citations

10.1136/jitc-2021-sitc2021.343

Gemcitabine (Gem) and nab-paclitaxel (NP) ± nivolumab (nivo) ± CD40 agonistic monoclonal antibody APX005M (sotigalimab), in patients (Pts) with untreated metastatic pancreatic adenocarcinoma (mPDAC): Phase (Ph) 2 final results.

Mark H. O’Hara, Eileen M. O’Reilly, Robert A. Wolff, Zev A. Wainberg, Andrew H. Ko et al. (20 authors)

Journal of Clinical Oncology2021-05-2023 citations

10.1200/jco.2021.39.15_suppl.4019

Baseline level and early on-treatment clearance of circulating mutant <i>KRAS</i> in metastatic pancreatic ductal adenocarcinoma treated with chemotherapy with or without immunotherapy.

Jacob E. Till, Aseel Abdalla, Neha Bhagwat, Taylor A. Black, Zhuoyang Wang et al. (20 authors)

Journal of Clinical Oncology2021-05-201 citations

10.1200/jco.2021.39.15_suppl.4122

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.

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.

2021-01-01233 citations

10.1016/s1470-2045(20)30532-5

Interventions

DRUGAPX005M

Administer intravenously once every 28-day Cycle

DRUGNivolumab

Administer intravenously twice every 28-day cycle

DRUGNab-Paclitaxel

Administer intravenously on 3 times every 28-day cycle

DRUGGemcitabine

Administer intravenously 3 times every 28-day cycle

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

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.

Design outcomes

Primary

Measure	Time frame	Description
Phase 1b Primary Safety Outcome	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	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.

Secondary

Measure	Time frame	Description
Disease Control Rate (DCR)	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)	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): DLT-Evaluable Population	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): Efficacy Population	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.
Objective Response Rate (ORR): Efficacy Population	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): DLT-Evaluable Population	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Phase 1b: Gem/NP/APX005M (0.1 mg/kg) Gemcitabine+Nab-Paclitaxel+APX005M (0.1 mg/kg) APX005M: Administer intravenously once every 28-day Cycle Nab-Paclitaxel: Administer intravenously on 3 times every 28-day cycle Gemcitabine: Administer intravenously 3 times every 28-day cycle	7
Phase 1b: Gem/NP/APX005M (0.3 mg/kg) Gemcitabine+Nab-Paclitaxel+APX005M (0.3 mg/kg) APX005M: Administer intravenously once every 28-day Cycle Nab-Paclitaxel: Administer intravenously on 3 times every 28-day cycle Gemcitabine: Administer intravenously 3 times every 28-day cycle	7
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg) Gemcitabine+Nab-Paclitaxel+nivolumab+APX005M (0.1 mg/kg) APX005M: Administer intravenously once every 28-day Cycle Nivolumab: Administer intravenously twice every 28-day cycle Nab-Paclitaxel: Administer intravenously on 3 times every 28-day cycle Gemcitabine: Administer intravenously 3 times every 28-day cycle	8
Phase 1b: Gem/NP/Nivolumab/APX005M (0.3 mg/kg) Gemcitabine+Nab-Paclitaxel+nivolumab+APX005M (0.3 mg/kg) APX005M: Administer intravenously once every 28-day Cycle Nivolumab: Administer intravenously twice every 28-day cycle Nab-Paclitaxel: Administer intravenously on 3 times every 28-day cycle Gemcitabine: Administer intravenously 3 times every 28-day cycle	8
Phase 2: Gem/NP/Nivolumab Gemcitabine+Nab-Paclitaxel+nivolumab Nivolumab: Administer intravenously twice every 28-day cycle Nab-Paclitaxel: Administer intravenously on 3 times every 28-day cycle Gemcitabine: Administer intravenously 3 times every 28-day cycle	37
Phase 2: Gem/NP/APX005M (0.3 mg/kg) Gemcitabine+Nab-Paclitaxel+APX005M (0.3 mg/kg) APX005M: Administer intravenously once every 28-day Cycle Nab-Paclitaxel: Administer intravenously on 3 times every 28-day cycle Gemcitabine: Administer intravenously 3 times every 28-day cycle	31
Phase 2: Gem/NP/Nivolumab/APX005M (0.3 mg/kg) Gemcitabine+Nab-Paclitaxel+nivolumab+APX005M (0.3 mg/kg) APX005M: Administer intravenously once every 28-day Cycle Nivolumab: Administer intravenously twice every 28-day cycle Nab-Paclitaxel: Administer intravenously on 3 times every 28-day cycle Gemcitabine: Administer intravenously 3 times every 28-day cycle	31
Total	129

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Overall Study	Death	5	5	7	4	23	23	24
Overall Study	Lost to Follow-up	0	0	0	1	1	2	0
Overall Study	Other	0	0	0	0	1	1	2
Overall Study	Remains on Study	2	2	0	1	7	5	3
Overall Study	Withdrawal by Subject	0	0	1	2	5	0	2

Baseline characteristics

Characteristic	Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Phase 1b: Gem/NP/Nivolumab/APX005M (0.3 mg/kg)	Phase 2: Gem/NP/Nivolumab	Phase 2: Gem/NP/APX005M (0.3 mg/kg)	Phase 2: Gem/NP/Nivolumab/APX005M (0.3 mg/kg)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	5 Participants	3 Participants	7 Participants	2 Participants	16 Participants	13 Participants	13 Participants	59 Participants
Age, Categorical Between 18 and 65 years	2 Participants	4 Participants	1 Participants	6 Participants	21 Participants	18 Participants	18 Participants	70 Participants
Age, Continuous	66.0 years	64.0 years	70.0 years	61.0 years	64.0 years	60.0 years	62 years	63.0 years
Cancer Location Pancreas Body	2 Participants	4 Participants	4 Participants	1 Participants	13 Participants	6 Participants	9 Participants	39 Participants
Cancer Location Pancreas Head	4 Participants	3 Participants	2 Participants	6 Participants	15 Participants	15 Participants	15 Participants	60 Participants
Cancer Location Pancreas Tail	1 Participants	0 Participants	2 Participants	1 Participants	9 Participants	10 Participants	7 Participants	30 Participants
Cancer Stage at Initial Diagnosis Stage 1	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants	4 Participants	5 Participants
Cancer Stage at Initial Diagnosis Stage 2	2 Participants	3 Participants	2 Participants	4 Participants	4 Participants	4 Participants	2 Participants	21 Participants
Cancer Stage at Initial Diagnosis Stage 3	1 Participants	0 Participants	0 Participants	0 Participants	3 Participants	1 Participants	1 Participants	6 Participants
Cancer Stage at Initial Diagnosis Stage 4	4 Participants	3 Participants	6 Participants	4 Participants	30 Participants	26 Participants	24 Participants	97 Participants
ECOG Performance Score ECOG Score = 0	3 Participants	1 Participants	5 Participants	4 Participants	17 Participants	19 Participants	14 Participants	63 Participants
ECOG Performance Score ECOG Score = 1	4 Participants	6 Participants	3 Participants	4 Participants	20 Participants	12 Participants	17 Participants	66 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants	2 Participants	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants	7 Participants	8 Participants	8 Participants	36 Participants	30 Participants	29 Participants	125 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Prior Treatment Prior Cancer Surgery No	4 Participants	4 Participants	7 Participants	4 Participants	26 Participants	23 Participants	26 Participants	94 Participants
Prior Treatment Prior Cancer Surgery Yes	3 Participants	3 Participants	1 Participants	4 Participants	11 Participants	8 Participants	5 Participants	35 Participants
Prior Treatment Prior Chemotherapy No	4 Participants	5 Participants	7 Participants	5 Participants	28 Participants	26 Participants	27 Participants	102 Participants
Prior Treatment Prior Chemotherapy Yes	3 Participants	2 Participants	1 Participants	3 Participants	9 Participants	5 Participants	4 Participants	27 Participants
Prior Treatment Prior Radiation No	6 Participants	7 Participants	7 Participants	5 Participants	30 Participants	30 Participants	29 Participants	114 Participants
Prior Treatment Prior Radiation Yes	1 Participants	0 Participants	1 Participants	3 Participants	7 Participants	1 Participants	2 Participants	15 Participants
Race/Ethnicity, Customized Race Asian	0 Participants	0 Participants	1 Participants	1 Participants	3 Participants	4 Participants	1 Participants	10 Participants
Race/Ethnicity, Customized Race Black or African American	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	2 Participants	1 Participants	5 Participants
Race/Ethnicity, Customized Race Other	0 Participants	0 Participants	0 Participants	0 Participants	2 Participants	1 Participants	3 Participants	6 Participants
Race/Ethnicity, Customized Race White	7 Participants	6 Participants	7 Participants	6 Participants	32 Participants	24 Participants	26 Participants	108 Participants
Sex: Female, Male Female	5 Participants	2 Participants	3 Participants	4 Participants	16 Participants	11 Participants	13 Participants	54 Participants
Sex: Female, Male Male	2 Participants	5 Participants	5 Participants	4 Participants	21 Participants	20 Participants	18 Participants	75 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	25 / 36	5 / 7	29 / 37	8 / 8	27 / 35
other Total, other adverse events	36 / 36	7 / 7	36 / 37	8 / 8	35 / 35
serious Total, serious adverse events	18 / 36	4 / 7	22 / 37	6 / 8	20 / 35

Outcome results

Primary

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.

Time frame: 1 year from initiation of study therapy

Population: The Efficacy Population is defined as (1) all patients who were randomized in Phase 2 and who received at least 1 dose of any study drug and (2) the 12 DLT-evaluable patients enrolled in Phase 1b at the recommended Phase 2 dose.

Arm	Measure	Value (NUMBER)
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	1-year Overall Survival Rate	0.577 probability
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	1-year Overall Survival Rate	0.481 probability
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	1-year Overall Survival Rate	0.413 probability

Comparison: Each treatment arm was analyzed independently and compared to a historical 1-year OS reference rate of 35%.p-value: 0.006z-test

Comparison: Each treatment arm was analyzed independently and compared to a historical 1-year OS reference rate of 35%.p-value: 0.062z-test

Comparison: Each treatment arm was analyzed independently and compared to a historical 1-year OS reference rate of 35%.p-value: 0.233z-test

Primary

Phase 1b Primary Safety Outcome

Number and percentage of subjects with adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)

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.

Population: The DLT-Evaluable Population is defined as all Phase 1b patients who received at least 2 doses of NP, at least 2 doses of Gem, and 1 dose of APX005M during Cycle 1.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Phase 1b Primary Safety Outcome	Dose-Limiting Toxicities (DLTs)	0 Participants
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Phase 1b Primary Safety Outcome	Adverse Events (AEs)	6 Participants
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Phase 1b Primary Safety Outcome	Serious Adverse Events (SAEs)	4 Participants
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Phase 1b Primary Safety Outcome	Serious Adverse Events (SAEs)	4 Participants
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Phase 1b Primary Safety Outcome	Adverse Events (AEs)	6 Participants
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Phase 1b Primary Safety Outcome	Dose-Limiting Toxicities (DLTs)	1 Participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Phase 1b Primary Safety Outcome	Dose-Limiting Toxicities (DLTs)	1 Participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Phase 1b Primary Safety Outcome	Adverse Events (AEs)	6 Participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Phase 1b Primary Safety Outcome	Serious Adverse Events (SAEs)	6 Participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.3 mg/kg)	Phase 1b Primary Safety Outcome	Serious Adverse Events (SAEs)	1 Participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.3 mg/kg)	Phase 1b Primary Safety Outcome	Adverse Events (AEs)	6 Participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.3 mg/kg)	Phase 1b Primary Safety Outcome	Dose-Limiting Toxicities (DLTs)	0 Participants

Secondary

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.

Time frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months.

Population: The Efficacy Population is defined as (1) all patients who were randomized in Phase 2 and who received at least 1 dose of any study drug and (2) the 12 DLT-evaluable patients enrolled in Phase 1b at the recommended Phase 2 dose.

Arm	Measure	Value (NUMBER)
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Disease Control Rate (DCR)	73.5 percentage of participants
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Disease Control Rate (DCR)	77.8 percentage of participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Disease Control Rate (DCR)	68.6 percentage of participants

Secondary

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.

Time frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 34.3 months.

Population: Patients in the DLT-Evaluable Population (defined as all Phase 1b patients who received at least 2 doses of NP, at least 2 doses of Gem, and 1 dose of APX005M during Cycle 1) and who achieved a Partial Response or Complete Response.

Arm	Measure	Value (MEDIAN)
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Duration of Response (DOR): DLT-Evaluable Population	15.51 months
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Duration of Response (DOR): DLT-Evaluable Population	7.03 months
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Duration of Response (DOR): DLT-Evaluable Population	9.07 months
Phase 1b: Gem/NP/Nivolumab/APX005M (0.3 mg/kg)	Duration of Response (DOR): DLT-Evaluable Population	10.35 months

Secondary

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.

Time frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months.

Population: Patients in the Efficacy Population (defined as all patients who were randomized in Phase 2 and who received at least 1 dose of any study drug and the 12 DLT-Evaluable patients enrolled in Phase 1b at the recommended Phase 2 dose) and who achieved a Partial Response or Complete Response.

Arm	Measure	Value (MEDIAN)
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Duration of Response (DOR): Efficacy Population	7.36 months
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Duration of Response (DOR): Efficacy Population	5.55 months
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Duration of Response (DOR): Efficacy Population	7.88 months

Secondary

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.

Time frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 34.3 months.

Population: The DLT-Evaluable Population is defined as all Phase 1b patients who received at least 2 doses of NP, at least 2 doses of Gem, and 1 dose of APX005M during Cycle 1.

Arm	Measure	Value (NUMBER)
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Objective Response Rate (ORR): DLT-Evaluable Population	66.7 percentage of participants
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Objective Response Rate (ORR): DLT-Evaluable Population	33.3 percentage of participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Objective Response Rate (ORR): DLT-Evaluable Population	66.7 percentage of participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.3 mg/kg)	Objective Response Rate (ORR): DLT-Evaluable Population	66.7 percentage of participants

Secondary

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.

Time frame: Initiation of study drug through radiographic progression or initiation of new anti-cancer therapy with a maximum exposure of 24.2 months.

Population: The Efficacy Population is defined as (1) all patients who were randomized in Phase 2 and who received at least 1 dose of any study drug and (2) the 12 DLT-evaluable patients enrolled in Phase 1b at the recommended Phase 2 dose (Arms B2 and C2).

Arm	Measure	Value (NUMBER)
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Objective Response Rate (ORR): Efficacy Population	50 percentage of participants
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Objective Response Rate (ORR): Efficacy Population	33.3 percentage of participants
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Objective Response Rate (ORR): Efficacy Population	31.4 percentage of participants

Secondary

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.

Time frame: Initiation of study drug through radiographic progression or death with a maximum exposure of 24.2 months.

Population: The Efficacy Population is defined as (1) all patients who were randomized in Phase 2 and who received at least 1 dose of any study drug and (2) the 12 DLT-evaluable patients enrolled in Phase 1b at the recommended Phase 2 dose.

Arm	Measure	Value (MEDIAN)
Phase 1b: Gem/NP/APX005M (0.1 mg/kg)	Progression-free Survival (PFS)	6.37 months
Phase 1b: Gem/NP/APX005M (0.3 mg/kg)	Progression-free Survival (PFS)	7.26 months
Phase 1b: Gem/NP/Nivolumab/APX005M (0.1 mg/kg)	Progression-free Survival (PFS)	6.74 months

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

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Duration of Response (DOR): DLT-Evaluable Population

Duration of Response (DOR): Efficacy Population

Objective Response Rate (ORR): DLT-Evaluable Population

Objective Response Rate (ORR): Efficacy Population

Progression-free Survival (PFS)