(2024) 22:365
Wei et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03581-y

BMC Medicine

RESEARCH ARTICLE

Open Access

Phase 1b study of first‑line fuzuloparibcombined with modified FOLFIRINOX followed
by fuzuloparib maintenance monotherapy
in pancreatic adenocarcinoma
Miaoyan Wei1,2,3,4†, Rujiao Liu2,5,6†, Yunyun Xu7†, Xiaobing Chen8†, Chao Liu9, Xueli Bai10, Xiaochen Zhang10,
Shuiping Gao2,5,6, Jialin Li1,2,3,4, Zhen Sheng11, Jianpo Lian11, Wenliang Wang11, Jian Zhang2,5,6, Si Shi1,2,3,4*,
Jin Xu1,2,3,4* and Xianjun Yu1,2,3,4*Abstract
Background Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX
in the locally advanced/metastatic (LA/M) setting.
Methods This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were
given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w
for 8–12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD)
and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D).
Results As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg
cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15
patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities.
Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0–74.0)
and disease control rate of 94.4% (95% CI, 72.7–99.9).
Conclusions First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe
and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID.

†

Miaoyan Wei, Rujiao Liu, Yunyun Xu, Xiaobing Chen contributed equally tothis work.
*Correspondence:
Si Shishisi@fudanpci.org
Jin Xuxujin@fudanpci.org
Xianjun Yu
yuxianjun@fudanpci.org
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
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Wei et al. BMC Medicine(2024) 22:365

Page 2 of 11

Trial registration ClinicalTrials.gov, NCT04228601.
Keywords Pancreatic cancer, Fuzuloparib, Chemotherapy, First-line, MaintenanceBackgroundPancreatic cancer is a highly lethal malignant tumor
and ranks as the seventh leading cause of cancer-related
deaths worldwide for both men and women [1]. It is
often asymptomatic at the early stage, and the deepseated location of the pancreas makes it difficult to detecttumors in this organ. As a result, a large proportion ofpatients present with advanced (30–35%) or metastatic(50–55%) disease at diagnosis, which unfortunately
eliminates the possibility of surgical resection [2–6].
Chemotherapy remains the standard first-line systemictreatment for pancreatic cancer, including AG (nabpaclitaxel plus gemcitabine), FOLFIRINOX (oxaliplatin,
irinotecan, leucovorin, and fluorouracil), and modified
FOLFIRINOX (mFOLFIRINOX) with reduced drug
doses. However, only 23–35% of unresectable patients
could achieve a response to these chemotherapy regimens, and the progression-free survival (PFS) and overall survival (OS) benefits are far from satisfactory [7–9].
Additional effective treatment strategies are urgently
needed.
Poly (adenosine diphosphate-ribose) polymerase (PARP)
inhibitors have been developed with the concept of synthetic lethality, by targeting tumor cells with a homologous recombination repair (HRR) deficiency. Mutations
in genes involved in HRR pathway have been identifiedin pancreatic cancer, such as BRCA1, BRCA2, ATM, andPALB2 [10–13], providing a strong rationale for the clinical investigation of PARP inhibitors for the treatment ofpancreatic cancer. In fact, olaparib has been approved
as maintenance therapy in patients with BRCA​-mutatedmetastatic pancreatic cancer who have response or stable disease after 4–6 months of first-line platinum-based
chemotherapy. Several single-agent PARP inhibitors
demonstrated modest activity in the later-line setting,with an objective response rate (ORR) ranging from 16%
to 22% [14–16]. However, mutations in the BRCA1/2
genes are present in only 5–9% of patients with pancreatic cancer [3, 17]. It has been reported that in otherspecific cancers, some patients without BRCA1/2 mutations also could respond to PARP inhibitors [18, 19]. Our
efforts are underway to ascertain the broad applicabilityof PARP inhibitors in pancreatic cancer.
Fuzuloparib, an orally administered PARP inhibitor, demonstrated almost complete inhibitor of PAR
formation and potent anti-tumor activity in preclinical models [20]. It has been approved in China as monotherapy for patients with germline BRCA​-mutatedplatinum-sensitive recurrent ovarian cancer and as maintenance therapy for patients with platinum-sensitive
recurrent ovarian cancer regardless of BRCA​ mutational
status [18, 21]. Given the potential synergistic effectbetween DNA-damaging agents and PARP inhibitors aswell as the effectiveness of PARP inhibitors as maintenance treatment in multiple cancer types [22–25], we initiated this study to explore the feasibility of fuzuloparibin combination with first-line mFOLFIRINOX followed
by fuzuloparib maintenance in patients with geneticallyunselected, locally advanced or metastatic pancreatic
adenocarcinoma.

Methods
Study design and treatment

This multicenter, phase 1b/2 study consisted of an openlabel, dose-escalation and -expansion, phase 1b portion
and a randomized, double-blind, placebo-controlled,phase 2 portion (ClinicalTrials.gov, NCT04228601).
Here, we reported the findings of the phase 1b portion.
In the dose-escalation phase, a standard 3 + 3 design
was adopted to assess the dose-limiting toxicity (DLT)and maximum tolerated dose (MTD) of fuzuloparib,
when combined with mFOLFIRINOX. Patients were
given fuzuloparib (planned escalating doses, 30, 60, 100,
and 150 mg; orally twice daily [BID]) in combination withmFOLFIRINOX regimen (oxaliplatin, 85 mg/m2, D1;
leucovorin, 400 mg/m2, D1; irinotecan, 150 mg/m2, D1;
and fluorouracil, 2400 mg/m2 given as a 46-h continuous
infusion; every 2 weeks) for 8 to 12 cycles, followed bymaintenance with fuzuloparib monotherapy at 150 mg
BID. Fixed dose of fuzuloparib was used for maintenance,as the MTD of single-agent fuzuloparib was determined
to be 150 mg BID, based on the results of the phase 1
clinical study of fuzuloparib in advanced solid tumors[26]. A treatment cycle was defined 2 weeks for boththe combination and maintenance therapy. DLTs wereobserved during the first 2 treatment cycles. During theobservation period, primary prophylaxis of neutropenia
with granulocyte colony-stimulating factor (G-CSF) was
not permitted. However, if grade ≥ 3 decreased neutrophil count occurred, administration of G-CSF (5 μg/kg/day) was recommended for symptomatic management,
as well as for prophylactic use in subsequent chemotherapy cycles.
In the dose-expansion phase, cohorts with the MTD
and lower dose of fuzuloparib would be expanded toWei et al. BMC Medicine(2024) 22:365

further collect safety, pharmacokinetics, and efficacy
data for the determination of recommended phase 2 dose
(RP2D). Primary prophylactic use of G-CSF was allowed.
The study treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal by
patient or investigator, whichever occurred first. Treatment interruptions and dose reduction of fuzulopariband mFOLFIRINOX were allowed to manage toxicities.
For fuzuloparib, each interruption should not exceed
14 days. For mFOLFIRINOX, resumption of treatment
within 7 days after interruption was recommended; if
the interruption lasted for more than 14 days, the investigator would judge, based on the benefit to the patient,
whether the patient should continue with the combination therapy or enter into the maintenance therapy withfuzuloparib alone.
Patient eligibility

Eligible patients were aged ≥ 18 years and had pathologically confirmed pancreatic adenocarcinoma with distant metastatic or locally advanced disease that was not
amenable to surgery, regardless of the mutation status ofhomologous recombination and DNA damage response
gene. Prior systemic anticancer therapies for pancreatic
adenocarcinoma were not permitted, with the exceptionof previous neoadjuvant or adjuvant chemotherapy completed at least 12 months before recurrence. All patientswere required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least
one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), alife expectancy of at least 6 months, and adequate organfunction. Key exclusion criteria included prior PARP
inhibitors; radiotherapy, investigational agents, or cellular therapies within 4 weeks prior to the start of study
treatment; radiological evidence of brain metastases; andactive hepatitis B or C virus infection.
Outcomes

Primary endpoints were DLT, MTD, and RP2D as determined by the safety monitoring committee and the sponsor. Secondary endpoints were safety, ORR, duration of
response (DoR), disease control rate (DCR), PFS, OS, andpharmacokinetic parameters. Exploratory endpoint was
carbohydrate antigen 19-9 (CA19-9) response rate.
Assessments

DLTs were defined as any of the following treatmentrelated adverse events (TRAEs): grade 2 cardiac insufficiency, renal impairment, or neurotoxicity; grade ≥ 3
non-hematological toxicity (with the exception of alopecia, controllable nausea or vomiting, pyrexia of known
causes such as tumor or infection, and laboratory

Page 3 of 11

abnormalities not requiring hospitalization); grade 4
decreased neutrophil count that persisted for ≥ 5 days
despite symptomatic treatment; grade 3 febrile neutropenia; grade 3 decreased platelet count with bleeding; grade
4 decreased platelet count; grade 4 anemia.
AEs were recorded from the time of informed consent
to 30 days after the last dose or until the start of a newantitumor therapy, whichever occurred earlier. TRAEs
were evaluated until 30 days after the last dose. All AEs
were graded according to the National Cancer InstituteCommon Terminology Criteria for Adverse Events, version 5.0.
Tumor responses were assessed using CT and MRI by
investigators at baseline and every 8 weeks after treatment, according to RECIST, version 1.1. Complete andpartial responses were required to be confirmed at least
4 weeks after the first documented response. Survival
was assessed every 2 months during follow-up.
The plasma concentrations of fuzuloparib were determined by using a validated high- performance liquid
chromatography coupled with tandem mass spectrometry. The mutation status for HRR genes (including
ATM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA,PALB2, RAD51B, RAD51C, RAD51D, and RAD54L) wastested using a custom-designed next-generation sequencing panel containing 1021 cancer-associated genes on a
DNBSEQ-T7RS sequencer. The serum CA19-9 levels
were monitored at baseline, every 4 weeks during treatment, and 30 days after the last dose of study treatment.
CA19-9 response was defined as a ≥ 50% decrease inCA19-9 occurring at any time point versus the baseline
value.
Statistical analysis

DLTs were assessed in all patients who enrolled in thedose-escalation phase, received at least one dose of study
treatment, and completed the 28-day evaluation period
or experienced any DLT during the period. Patients had
to receive ≥ 75% of the dose of assigned therapy during the DLT observation period to be evaluable for DLT
assessment. Safety, efficacy, and pharmacokinetics wereanalyzed in patients who received at least one dose of
study treatment and had at least one corresponding postbaseline evaluation. CA19-9 response was assessed inpatients with a CA19-9 level exceeded twice the upper
limit of the normal range at baseline who received at least
one dose of study treatment and had at least one postbaseline evaluation.
AEs were summarized descriptively. The point estimates of ORR, DCR, and CA19-9 response rate as well as
their two-sided 95% CIs were calculated using the Clopper-Pearson method. Time-to-event outcomes including
DoR, PFS and OS were estimated using the Kaplan-MeierWei et al. BMC Medicine(2024) 22:365

method, and their two-sided 95% CIs were calculatedon the basis of the Brookmeyer-Crowley method. For
patients without progression or death, PFS was censoredon the date of the last imaging examination. For patients
who had disease progression or died after missing two
or more consecutive tumor response assessments, PFS
was censored on the date of the last imaging examination
before the missing visits. Pharmacokinetic parameters of
fuzuloparib following single administration were determined by non-compartmental analysis methods using
Phoenix WinNonlin, version 8.0 or above. Other analyses
were done using SAS, version 9.4.

Results
Patients and treatment

Between May 7, 2020 and Dec 20, 2021, a total of 39 eligible patients were recruited from 6 study sites in China,
and all were administrated with at least one dose of trial
therapy (Fig. 1). The demographic and clinical characteristics of patients at baseline are shown in Table 1.
Most patients had an ECOG performance status of 1
(34, 87.2%). 24 (61.5%) patients were male. 35 (89.7%)
patients had metastases, with the most common sites
being liver (28, 71.8%), regional lymph nodes (16, 41.0%),
peritoneum (5, 12.8%), and lung (4, 10.3%). HRR geneFig. 1 Trial profile. CA19-9, carbohydrate antigen 19-9

Page 4 of 11

mutations were detected in 5 (12.8%) patients, including
2 (5.1%) with germline mutation in ATM, 1 (2.6%) withsomatic mutation in ATM, 1 (2.6%) with somatic mutation in BRCA1 and CHEK2, and 1 (2.6%) with germline
mutation in FANCA.
As of data cutoff on Jan 15, 2023, the median followup duration was 11.4 months (range, 0.3–32.0). Of theenrolled 39 patients, 38 discontinued all study treatment
components, mainly due to radiographical progression(Fig. 1).
Tolerability

In the dose-escalation phase, 12 patients were enrolled(4 in the 30 mg cohort, 6 in the 60 mg cohort, and 2 in
the 100 mg cohort). DLTs were observed in one of the 6patients in the 60 mg cohort (grade 4 decreased platelet
count and grade 4 decreased neutrophil count lastingfor ≥ 5 d) and 1 of the 2 patients in the 100 mg cohort(grade 4 decreased neutrophil count lasting for ≥ 5 d;Additional file 1: Table S1). Another patient in the 100 mg
cohort experienced grade 4 decreased neutrophil countand grade 3 decreased platelet count during the firsttreatment cycle, and study treatment was interrupted due
to AEs in this patient. Thus, enrollment for the 100 mg
cohort was halted, dose escalation was terminated (noWei et al. BMC Medicine(2024) 22:365

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Table 1 Patient demographics and clinical characteristics at baseline

Age, years

30 mg BID (n = 15)60 mg BID (n = 22)

100 mg BID (n = 2)

Overall (N = 39)

57.0 (31.0–71.0)

57.5 (32.0–74.0)

45.0 (37.0–53.0)

57.0 (31.0–74.0)

Sex
Male

9 (60.0)

13 (59.1)

2 (100.0)

24 (61.5)

Female6 (40.0)9 (40.9)015 (38.5)

ECOG performance status0

2 (13.3)

3 (13.6)0

5 (12.8)

1

13 (86.7)

19 (86.4)

2 (100.0)34 (87.2)

Pancreatic tumor location
Head

5 (33.3)

7 (31.8)0

12 (30.8)

Body

4 (26.7)

6 (27.3)

1 (50.0)

11 (28.2)

Tail

6 (40.0)

8 (36.4)

1 (50.0)

15 (38.5)

Multicentric01 (4.5)0

1 (2.6)

Disease characteristics
Metastatic

13 (86.7)

20 (90.9)

2 (100.0)35 (89.7)

Locally advanced

4 (26.7)2 (9.1)0

6 (15.4)

Number of organs with metastasesa
0

4 (26.7)2 (9.1)0

6 (15.4)

1

6 (40.0)

12 (54.5)

2 (100.0)

20 (51.3)

2

1 (6.7)5 (22.7)0

6 (15.4)3

4 (26.7)

3 (13.6)0

7 (17.9)

Common metastatic sites (≥ 10%)Liver

10 (66.7)

16 (72.7)

2 (100.0)

28 (71.8)

Regional lymph nodes

7 (46.7)

8 (36.4)

1 (50.0)

16 (41.0)

Peritoneum

3 (20.0)

2 (9.1)0

5 (12.8)Lung

1 (6.7)

3 (13.6)

04 (10.3)

CA19-9 level
Normal4 (26.7)

5 (22.7)09 (23.1)

Elevated, < 59xULN

5 (33.3)

11 (50.0)

1 (50.0)

17 (43.6)

Elevated, ≥ 59xULN

1 (6.7)

3 (13.6)

04 (10.2)

Unknown

5 (33.3)

3 (13.6)

1 (50.0)9 (23.1)

HRR gene mutations

2 (13.3)c

3 (13.6)d0

5 (12.8)

Previous surgery

0

1 (4.5)0

1 (2.6)b

Data are median (range) or n (%)
ECOG Eastern Cooperative Oncology Group, CA19-9 Carbohydrate antigen 19-9, HRR Homologous recombination repaira

did not include regional lymph nodes metastases. bpalliative surgery. c1 with germline mutation in ATM and 1 with germline mutation in FANCA; d1 with germline
mutation in ATM, 1 with somatic mutation in ATM, and 1 with somatic mutation in BRCA1 and CHEK2

patient was enrolled in the 150 mg cohort), and 60 mg
BID was established as the MTD. Subsequently, 60 and
30 mg cohorts were expanded to 22 and 15 patients,
respectively.
Pharmacokinetics

Pharmacokinetic characteristics of fuzuloparib, whencombined with mFOLFIRINOX, were available in all 39
patients enrolled in the dose-escalation and dose-expansion phases. Plasma fuzuloparib level showed an increasing trend with ascending dose (Additional file 1: Fig. S1).
In the 30, 60, and 100 mg cohorts, the geometric mean

maximum plasma concentrations of fuzuloparib were
992 ng/mL (percentage geometric coefficient of variation [GeoCV%], 47.5%), 1940 ng/mL (GeoCV%, 47.7%),
and 3320 ng/mL (GeoCV%, 11.3%); the geometric mean
area under the curve from the first dose to 10 h thereafter were 6140 h*ng/mL (GeoCV%, 42.9%), 11,900 h*ng/
mL (GeoCV%, 46.6%), and 19,800 h*ng/mL (GeoCV%,
4.5%); and the median of time to peak fuzuloparib
concentration after single administration were 3.00 h(range, 0.98–10.00), 2.99 h (range, 0.98–6.07), and 4.51 h(range, 2.97–6.05), respectively. The geometric mean
steady-state trough concentrations of fuzuloparib wereWei et al. BMC Medicine(2024) 22:365

Page 6 of 11699 ng/mL (GeoCV%, 80.6%) with 30 mg BID, 1310 ng/
mL (GeoCV%, 74.6%) with 60 mg BID, and 883 ng/mL(GeoCV%, 6549.7%) with 100 mg BID.

Additional file 1: Table S3). The median relative dose
intensity of fuzuloparib during maintenance was 96.0%,
with similar values among the 3 cohorts.

Treatment exposure

The median cycle of combination treatment was 7 (range,
1–12). Exposure of the individual components during
combination of fuzuloparib and mFOLFIRINOX areshown in Additional file 1: Table S2. The median relative dose intensity of fuzuloparib during combination in
all patients was 84.6%, with the highest value observedin the 60 mg cohort (90.3%). The median relative dose
intensities of chemotherapeutic agents ranged from
91.4% to 95.2%, with no obvious differences among the 3cohorts.
After completing the combination treatment without
disease progression, 21 patients received maintenancefuzuloparib (including 7 in the 30 mg cohort, 13 in the
60 mg cohort, and 1 in the 100 mg cohort), with a mediantreatment duration of 11.9 weeks (range, 1.3–107.9;

SafetyAll 39 patients were included for safety assessment.
Grade ≥ 3 TRAEs were reported in 34 (87.2%) patients.
The most common TRAEs of grade 3 or 4 were hematologic toxicities, including decreased neutrophil count,decreased platelet count, decreased white blood cellcount, and anemia (Table 2).
TRAEs led to interruption of any study treatment component in 33 (84.6%) patients. Dose reduction of any
study treatment component due to TRAEs occurred in
22 (56.4%) patients, with 10 (25.6%) patients due to AEs
related to fuzuloparib and 19 (48.7%) due to AEs related
to mFOLFIRINOX (Additional file 1: Table S4).
Five (12.8%) patients discontinued treatment becauseof TRAEs, including decreased platelet count in 3 (7.7%)

Table 2 Common TRAEs
30 mg BID (n = 15)60 mg BID (n = 22)

Overall (N = 39)

All gradeAll gradeAll grade

Grade ≥ 3

Grade ≥ 3

Grade ≥ 3

Anemia14 (93.3)

3 (20.0)

20 (90.9)

10 (45.5)

36 (92.3)

13 (33.3)

Neutrophil count decreased

13 (86.7)

11 (73.3)

20 (90.9)

13 (59.1)

35 (89.7)

26 (66.7)

White blood cell count decreased

13 (86.7)

6 (40.0)

18 (81.8)

10 (45.5)

33 (84.6)

17 (43.6)

Platelet count decreased

10 (66.7)

6 (40.0)

16 (72.7)

11 (50.0)

28 (71.8)

18 (46.2)

Weight decreased

9 (60.0)0

16 (72.7)

1 (4.5)26 (66.7)

1 (2.6)

Vomiting

10 (66.7)

1 (6.7)

12 (54.5)

024 (61.5)

1 (2.6)

Aspartate aminotransferase increased

11 (73.3)

0

10 (45.5)

023 (59.0)0

Nausea11 (73.3)

0

11 (50.0)023 (59.0)0Asthenia

12 (80.0)

1 (6.7)

10 (45.5)

1 (4.5)22 (56.4)

2 (5.1)

Decreased appetite

9 (60.0)011 (50.0)

1 (4.5)21 (53.8)

1 (2.6)

Alanine aminotransferase increased

8 (53.3)

1 (6.7)

10 (45.5)

020 (51.3)

1 (2.6)

Hyponatremia

9 (60.0)

2 (13.3)

10 (45.5)

2 (9.1)19 (48.7)

4 (10.3)

Alopecia

8 (53.3)

07 (31.8)

0

16 (41.0)0

Diarrhea

6 (40.0)0

6 (27.3)

0

14 (35.9)

2 (5.1)

Hypokalemia

5 (33.3)

3 (20.0)9 (40.9)

3 (13.6)

14 (35.9)

6 (15.4)

Hypoalbuminemia

4 (26.7)09 (40.9)013 (33.3)0Peripheral sensory neuropathy

5 (33.3)

0

6 (27.3)

0

12 (30.8)

0Proteinuria

4 (26.7)07 (31.8)011 (28.2)

0

Blood bilirubin increased

4 (26.7)05 (22.7)09 (23.1)

0Constipation

4 (26.7)05 (22.7)09 (23.1)

0

Mouth ulceration

7 (46.7)

01 (4.5)0

9 (23.1)

0

Lymphocyte count decreased

4 (26.7)

1 (6.7)4 (18.2)

3 (13.6)

8 (20.5)

4 (10.3)

Stomatitis

2 (13.3)

0

6 (27.3)08 (20.5)

0

Hypocalcemia

2 (13.3)

0

6 (27.3)08 (20.5)

0

Pyrexia

4 (26.7)

04 (18.2)

08 (20.5)

0Data are n (%). Table lists TRAEs of any grade that occurred in at least 20% of the safety population of 39 patients and corresponding TRAEs of grade 3 or 4. Grade 5
TRAE occurred in 1 (2.6%) patient, which was septic shock. TRAE, treatment-related adverse event

Wei et al. BMC Medicine(2024) 22:365

patients, septic shock in 1 (2.6%), and neurotoxicity in 1
(2.6%). All of these AEs were related to mFOLFIRINOX,
and only septic shock was also related to fuzuloparib.
Twenty-four (61.5%) patients experienced serious
TRAEs (Additional file 1: Table S5), mainly including decreased neutrophil count in 12 (30.8%) patients,
decreased platelet count in 8 (20.5%), febrile neutropenia in 6 (15.4%), decreased white blood cell count in 5
(12.8%), and anemia in 4 (10.3%). One (2.6%) patient had
treatment-related death, caused by septic shock.
Efficacy

Of enrolled 39 patients, 7 patients were unevaluablefor tumor response due to the absence of post-baseline
assessments. Among the 32 patients who had post-baseline assessments for tumor response, shrinkage in target
lesions was observed in 26 (81.3%) patients (Fig. 2A).
The ORR in overall population was 34.4% (11/32; 95%
CI, 18.6–53.2), and DCR was 87.5% (28/32; 95% CI,
71.0–96.5; Table 3). Substantial reductions in tumor
burden were durable (Fig. 2B and C). Median DoR was
7.5 months (95% CI, 3.5–not reached).
A total of 24 of 39 (61.5%) patients had disease progression or died, and median PFS was 7.3 months (95%CI, 5.3–10.1; Fig. 3A). Twenty-six (66.7%) patients had
died, and median OS was 11.5 months (95% CI, 7.8–14.2;
Fig. 3B). CA19-9 responses were evaluable in 26 patients,and 57.7% (95% CI, 36.9–76.7) of patients had a CA19-9
response (Additional file 1: Table S6).
Generally, efficacy in 60 mg cohort seemed to be mostfavorable, with an ORR of 50.0% (9/18; 95% CI, 26.0–
74.0), DCR of 94.4% (17/18; 95% CI, 72.7–99.9), medianPFS of 7.2 months (95% CI, 5.1–13.9), median OS of
12.5 months (95% CI, 7.8–not reached), and CA19-9
response rate of 71.4% (95% CI, 41.9–91.6) (Table 3,
Additional file 1: Fig. S2, and Additional file 1: Table S6).
Combined with the safety, tolerability, pharmacokinetics, and clinical activity findings, 60 mg BID was established as the RP2D of fuzuloparib when combined withmFOLFIRINOX.

Discussion
To the best of our knowledge, this study is the first toreport the addition of a PARP inhibitor to standard firstline therapy and its continued use as maintenance therapy in patients with advanced or metastatic pancreaticcancer. Fuzuloparib at 30 or 60 mg BID combined withmFOLFIRINOX for 8 to 12 cycles followed by maintenance with fuzuloparib at 150 mg BID was generally safe.
The most common TRAEs were hematological toxicities. When combined with mFOLFIRINOX, 60 mg BID
fuzuloparib exhibited the most favorable activity, with an

Page 7 of 11

ORR of 50.0% and DCR of 94.4%, and was established as
the RP2D.
An important consideration for the design of this study
was the choice of chemotherapy regimen to be used in
combination. Anti-cancer platinum drugs, such as cisplatin and oxaliplatin, exert their cytotoxic action by covalently binding to the DNA strand, which leads to DNA
damage in tumor cells. PARP is involved in DNA repair.
Inhibitors targeting PARP can further impair the abilityof cancer cells to repair DNA damage, thereby enhancing
the cytotoxic effects of platinum-based chemotherapeutic regimens. Therefore, we selected the mFOLFIRINOX
in order to maximize the efficacy and safety. Fuzuloparib
at 60 mg BID combined with mFOLFIRINOX achieved
an ORR of 50.0% (first response in all responders
occurred during the combination), which was numerically superior to historical data of standard chemotherapeutic regimens (23% [99/431] with GA, 31.6% [54/171]
with FOLFIRINOX, and 35.1% [13/37] with mFOLFIRINOX) [7–9].
There were several early-phase clinical trials assessing PARP inhibitors combined with chemotherapeutic
agents as front-line treatment for pancreatic cancer. In
an expansion cohort of a phase 1 study in patients withgenetically unselected, advanced or metastatic disease,olaparib plus gemcitabine had an ORR of 27% (4/15),
compared with 14% (1/7) with gemcitabine alone [27].
Veliparib in combination with 5-fluorouracil and oxaliplatin demonstrated an ORR of 40% (6/15) in patientswith known pathogenic HRR mutations or a family history suggestive of a breast or ovarian cancer syndrome
in a phase 1/2 study [28]. Similarly, a phase 1 study ofveliparib in combination with gemcitabine and cisplatin
reported an ORR of 41.2% (7/17) [22]. However, this
triple-combination therapy did not show any improvement in ORR, PFS, or OS compared to gemcitabineand cisplatin [29]. Our study was the first to explore theanti-tumor activity of combining a PARP inhibitor withmFOLFIRINOX, and the results indicated that FOLFOXbased chemotherapy might be a better choice.
Additionally, transitioning patients to maintenancetherapy with a single-agent PARP inhibitor after achieving a tumor response or stable disease with combination therapy perhaps represents a favorable treatment
strategy. Such a strategy was proven to be effective inthe VELIA/GOG-3005 phase 3 study of ovarian cancer,
where veliparib plus chemotherapy followed by veliparib
maintenance therapy led to significantly longer PFS thanchemotherapy alone in the BRCA​-mutation cohort, HRR
gene mutation cohort, and the overall population [30].
We also used this scheme in this study. First-line fuzuloparib at 60 mg BID combined with mFOLFIRINOX followed by maintenance with fuzuloparib at 150 mg BID

Wei et al. BMC Medicine(2024) 22:365

Page 8 of 11

Fig. 2 Tumor responses. A Best percentage change from baseline in the sum of perpendicular diameters of target lesions. B Percentage change
from baseline in target lesion tumor burden over time. C Tumor responses per RECIST v1.1 over time. *confirmed responses. BID, twice daily; HRR,
homologous recombination repair

showed a median PFS of 7.2 months and a median OS of
12.5 months, only slightly longer than FOLFIRINOX andmFOLFIRINOX [7, 8]. However, this was an early-phasestudy with exploratory nature. Whether patients cantruly benefit from fuzuloparib plus mFOLFIRINOX followed by fuzuloparib maintenance, and the contributionsof fuzuloparib during combination and maintenancetreatment period, still need to be investigated in largescale randomized trials with appropriated controls.
The safety profile was similar with that of fuzuloparib
monotherapy and mFOLFIRINOX [8, 18, 21]. No unexpected TRAEs were observed. A total of 12.8% of patientspermanently discontinued the study treatment due to
TRAEs; among them, only septic shock was deemed toWei et al. BMC Medicine(2024) 22:365

Page 9 of 11

Table 3 Tumor response
30 mg BID (n = 12)60 mg BID (n = 18)

100 mg BID (n = 2)

Overall (N = 32)

Best overall response, n (%)
Partial response

2 (16.7)

9 (50.0)011 (34.4)

Stable disease

8 (66.7)

8 (44.4)

1 (50.0)

17 (53.1)

Progressive disease
Confirmed ORR, % (95% CI)

2 (16.7)

1 (5.6)

1 (50.0)

4 (12.5)

16.7 (2.1–48.4)

50.0 (26.0–74.0)

0 (0–84.2)

34.4 (18.6–53.2)

Confirmed DCR, % (95% CI)

83.3 (51.6–97.9)

94.4 (72.7–99.9)

50.0 (1.3–98.7)

87.5 (71.0–96.5)

DoR, median (95% CI), months

23.4 (18.9–NR)

5.5 (3.5–NR)

NA

7.5 (3.5–NR)

Tumor response was assessed in the evaluable set. Seven patients had no post-baseline assessments for tumor response, including 4 patients who withdrew from thestudy by their own decision, 2 due to adverse events, and 1 due to investigator decision
BID Twice daily, ORR Objective response rate, DCR Disease control rate, DoR Duration of response, NA Not applicable, NR Not reachedFig. 3 Kaplan-Meier estimates of progression-free survival (A) and overall survival (B) in overall population

be related to both fuzuloparib and mFOLFIRINOX by
the investigator, while others were considered related
to mFOLFIRINOX. Addition of fuzuloparib to mFOLFIRINOX resulted in a high incidence of hematological toxicities, including decreased neutrophil count,decreased platelet count, decreased white blood cellcount, and anemia, which required strict monitoring andconsideration of pharmacological prophylaxis in subsequent trials.

Conclusions
In summary, first-line fuzuloparib plus mFOLFIRINOX
followed by fuzuloparib maintenance was generally safe,with no unexpected toxicities, and showed encouraging

Wei et al. BMC Medicine(2024) 22:365

efficacy in advanced or metastatic pancreatic adenocarcinoma. Particularly, the administration of fuzuloparib
at 60 mg BID demonstrated enhanced anti-tumor activity when combined with mFOLFIRINOX, indicatingthat this combination might be effective as neoadjuvant
therapy and thereby potentially beneficial for surgicalresection. A phase 1 study of fuzuloparib in combination
with mFOLFIRINOX in patients with resectable pancreatic cancer is ongoing (ClinicalTrials.gov Identifier:
NCT04425876).
Abbreviations
AG	Nab-paclitaxel plus gemcitabine
BID	Twice daily
CA19-9	Carbohydrate antigen 19-9
DCR	Disease control rate
DLT	Dose-limiting toxicity
DoR	Duration of response
ECOG	Eastern Cooperative Oncology GroupFOLFIRINOX	Oxaliplatin, irinotecan, leucovorin, and fluorouracil
HRR	Homologous recombination repair
MTD	Maximum tolerated dose
ORR	Objective response rate
OS	Overall survival
PARP	Poly (adenosine diphosphate-ribose) polymerase
PFS	Progression-free survival
RP2D	Recommended phase 2 dose
TRAEs	Treatment-related adverse events

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03581-y.
Additional file 1: Fig. S1. Pharmacokinetic profiles of fuzuloparib, whencombined with mFOLFIRINOX. Fig. S2. Kaplan-Meier estimates of progression-free survival (A) and overall survival (B) in 30 and 60 mg BID cohorts.
Table S1. Dose-limiting toxicities. Table S2. Exposure of the individual components during combination of fuzuloparib and modified FOLFIRINOX.
Table S3. Exposure of fuzuloparib during maintenance. Table S4. Safetysummary. Table S5. Treatment-related serious adverse events. Table S6.
CA19-9 response rate.
Acknowledgements
This study was funded by Jiangsu Hengrui Pharmaceuticals. We are gratefulto all patients and their families, the investigators, and the site staff. We thankYisong Liu (Beijing Improve-Quality Tech.) for his input in statistical analyses.
Medical writing support was provided by Hui Dong (Medical Writer at Hengrui) according to Good Publication Practice Guidelines.
Authors’ contributions
MW: Data curation, Investigation, Methodology, Validation, Writing – originaldraft. RL: Data curation, Investigation, Methodology, Validation, Writing –review & editing. YX: Data curation, Investigation, Methodology, Validation,
Writing – review & editing. XC: Data curation, Investigation, Methodology,
Validation, Writing – review & editing. CL: Data curation, Investigation, Methodology, Validation, Writing – review & editing. XB: Data curation, Investigation, Methodology, Validation, Writing – review & editing. XZ: Data curation,
Investigation, Methodology, Validation, Writing – review & editing. SG: Data
curation, Investigation, Methodology, Validation, Writing – review & editing.
JL1: Data curation, Investigation, Methodology, Validation, Writing – review& editing. ZS: Formal Analysis, Methodology, Software, Validation, Visualization, Writing – review & editing. JL2: Methodology, Project administration,
Resources, Validation, Writing – review & editing. WW: Methodology, Project
administration, Resources, Validation, Writing – review & editing. JZ: Data
curation, Investigation, Methodology, Validation, Writing – review & editing.

Page 10 of 11

SS: Data curation, Investigation, Methodology, Validation, Writing – review &editing. JX: Data curation, Investigation, Methodology, Validation, Writing –review & editing. XY: Conceptualization, Investigation, Methodology, Project
administration, Resources, Supervision, Validation, Writing – review & editing.
All authors read and approved the final manuscript.
Funding
Jiangsu Hengrui Pharmaceuticals Co., Ltd.
Availability of data and materials
The individual patient data generated during this study will be considered forsharing after the product and indication have been approved by major healthauthorities. Data may be request 24 months after study completion. Qualified
researchers should submit a proposal to the corresponding author outlining
the reasons for requiring the data. The sponsor will provide the data if the proposal is approved, provided that the requestor signs a data-access agreement.
Use of data must comply with the requirements of Human Genetics Resources
Administration of China and other country or region-specific regulations.

Declarations
Ethics approval and consent to participate
The protocol and all amendments were approved by the Ethics Committeeof Fudan University Shanghai Cancer Center (1911210-13-2108C), Zhejiang Provincial People’s Hospital (2020YW011-A3), Henan Cancer Hospital(2020011002), Sun Yat-sen Memorial Hospital (2020-YW-025-004), and theFirst Affiliated Hospital, Zhejiang University School of Medicine (2021-573).
The study was conducted in accordance with the Declaration of Helsinki
and Good Clinical Practice guidelines. All patients provided written informed
consent.
Consent for publication
Not applicable.
Competing interests
Zhen Sheng, Jianpo Lian, and Wenliang Wang report being employed by
Jiangsu Hengrui Pharmaceuticals. All other authors declare no competinginterests.
Author details
1
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center,No.270 Dong’An Road, Shanghai 200032, China. 2 Department of Oncology,
Shanghai Medical College, Fudan University, Shanghai, China. 3 Shanghai
Pancreatic Cancer Institute, Shanghai, China. 4 Pancreatic Cancer Institute,
Fudan University, Shanghai, China. 5 Department of Medical Oncology, Fudan
University Shanghai Cancer Center, Shanghai, China. 6 Department of Phase
I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai,
China. 7 Department of General Surgery, Cancer Center, Division of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, AffiliatedPeople’s Hospital, Hangzhou Medical College, Hangzhou, China. 8 Department
of Internal Oncology, Henan Cancer Hospital, Zhengzhou, China. 9 Department
of Hepato‑Pancreato‑Biliary Surgery, Sun Yat-Sen Memorial Hospital, Guangzhou, China. 10 Department of Medical Oncology, The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou, China. 11 Clinical Researchand Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.
Received: 18 January 2024 Accepted: 22 August 2024

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