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A Phase I Study of FOLFIRINOX Plus IPI-926 for Advanced Pancreatic Adenocarcinoma

Phase 1
18 Years
Open (Enrolling)
Pancreatic Cancer, Adenocarcinoma, Pancreatic Neoplasms

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Trial Information

A Phase I Study of FOLFIRINOX Plus IPI-926 for Advanced Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related
mortality in the United States, with an estimated 36,800 deaths attributable to PDAC in
2010.(1) Over 90% of patients have inoperable disease at presentation, at which point
systemic therapy becomes the primary form of treatment. Single agent gemcitabine became the
standard of care for advanced pancreatic cancer a decade ago since demonstrating improved
survival when compared with fluorouracil. Since then, a number of phase III trials have
evaluated the benefit of adding additional cytotoxic or targeted agents to gemcitabine, as
shown in the table below. The PA.3 trial(2), which led to the approval of erlotinib in
advanced pancreatic cancer, was a landmark study in that it represented the first positive
phase III study of a combination regimen for this disease indication; however, while
erlotinib represents both an important proof of principle and a welcome addition to our
therapeutic armamentarium, it has failed to gain significant traction in this disease, as
many in the oncology community consider the marginal absolute improvement in median overall
survival to be of questionable clinical significance.

FOLFIRINOX: A new standard of care for advanced PDAC? At the 2010 American Society of
Clinical Oncology Annual Meeting (ASCO), a French cooperative group presented results of a
potentially practice-changing phase III clinical trial (PRODIGE 4/ACCORD 11).(18) In this
study, 342 patients with previously untreated metastatic pancreatic cancer were randomized
to receive either gemcitabine monotherapy or the combination of biweekly infusional
5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) (ref). The
investigators reported statistically significant improvements for the FOLFIRINOX arm in the
primary endpoint, overall survival (median of 11.1 months vs 6.8 months, P < .0001); as well
as 1-year survival rate (48.4% vs. 20.6%), median progression-free survival (6.4 vs. 3.3
months; P < .0001), and objective response rate (CR+PR, 31.6% vs. 9.4%; P = .0001)). Not
surprisingly, the more complex FOLFIRINOX regimen was associated with higher rates of grade
3/4 toxicities, including neutropenia (45.7% vs 18.7%), febrile neutropenia (5.4% vs. 0.6%),
fatigue (23.2% vs. 14.2%), and diarrhea (12.7% vs. 1.2%). Notably, while primary prophylaxis
with growth factor support was not mandated in this trial, 42.5% of patients did ultimately
receive such support. Moreover, most patients enrolled in this trial had non-pancreatic head
tumors (approximately 64%) which is the opposite distribution of what one might expect in a
representative pancreatic cancer population. Thus, it is conceivable that the FOLFIRINOX
regimen, with its high rates of neutropenia, may lead to unacceptable rates of infectious
complications (eg, ascending cholangitis and biliary sepsis), in patients with pancreatic
head tumors with indwelling endobiliary stents.

Nevertheless, this strikingly positive survival benefit, with a median overall survival
approaching one year in a purely metastatic cohort, has never before been observed in any
previous study, which raises the question of whether FOLFIRINOX should become the newly
adopted standard of care, at least in patients with preserved performance status (patients
on this trial were required to have an ECOG performance score of 0-1).

HEDGEHOG SIGNALING The Hedgehog(19) signaling pathway is important for normal mammalian
embryonic development and for adult tissue remodeling. Recent reports have demonstrated that
aberrant activation of the Hh pathway is associated with many types of cancer, including
basal cell carcinoma (BCC), medulloblastoma, pancreatic adenocarcinomas, small-cell lung
cancer (SCLC), metastatic prostate cancer, glioma, breast cancer, hepatocellular cancer, and
hematologic malignancies. High levels of Hh pathway activation, either through mutation of
pathway components or through constitutive expression of Hh pathway genes, appear to be
involved in both the initiation of cancer and tumor cell survival, as well as tumor growth
and metastasis. Given the therapeutic potential of Hh pathway inhibition in cancer, Infinity
has developed IPI-926, a potent and specific antagonist of the Hh pathway that binds
Smoothened (Smo), a key signaling transmembrane protein in this pathway, thereby diminishing
downstream promoters of cellular proliferation.

Pancreatic adenocarcinomas are an ideal tumor class in which to evaluate the activity of a
Hh pathway inhibitor, as multiple lines of evidence support a role for Hedgehog signaling in
pancreatic tumorigenesis:

- Aberrant expression of Sonic hedgehog (SHH) and its associated signaling components
(patched (PTC) and smoothened (SMO)) are frequently found in pancreatic cancer

- Pharmacologic inhibition of hedgehog signaling produces antitumor effects in pancreatic
cancer cell lines27 and orthotopic xenograft models.(28,29) Studies involving global
sequencing analysis have identified this pathway as one of the central elements
undergoing transformation in nearly all pancreatic cancers.(21)

- Hedgehog signaling may play an important role in maintenance of pancreatic cancer stem

- The dense desmoplastic mesenchymal network that constitutes the stroma of pancreatic
adenocarcinomas coupled with poor vascularity may present a major challenge to
effective delivery of intravenous chemotherapy to the bulk of pancreatic tumor cell
burden. Recent evidence in a genetically engineered mouse model of pancreatic cancer
demonstrated that IPI-926 can deplete tumor-associated stromal tissue and increase
intratumoral mean vessel density, resulting in enhanced delivery of concurrently
administered systemic agents such as gemcitabine, decreased tumor burden, and prolonged

Inclusion Criteria:

1. Histologically-confirmed pancreatic adenocarcinoma

2. Disease that is not operable (locally advanced or metastatic)

3. No prior systemic therapy for their diagnosis (except in adjuvant setting > 6 months

4. ECOG performance score of 0-1

5. At least 18 years of age

6. Evidence of either or both of the following:

- RECIST-defined measurable disease (lesions that can be accurately measured in at
least one dimension with the longest diameter ≥ 20mm using conventional
techniques or ≥10 mm with spiral CT scan)

- An elevated serum CA19-9 at baseline ( ≥ 2X ULN)

7. Endobiliary stents, but not percutaneous biliary drains, are permissible.

8. Adequate bone marrow function:

- ANC ≥ 1500/uL

- platelet count ≥ 100,000/uL

- hemoglobin ≥ 9.0 g/dL (may be increased to this level with transfusion as long
as there is no evidence of active bleeding)

9. Adequate hepatic function:

- Total bilirubin ≤ 1.5 X ULN

- AST (SGOT) ≤ 2.5 X ULN

- ALT (SGPT) ≤ 2.5 X ULN

10. Adequate renal function as determined by either:

- Calculated or measured creatinine clearance ≥ 40 mL/min (for calculated
creatinine clearance, Cockcroft-Gault equation will be used). The Modified
Cockcroft-Gault formula is as follows:

[140 - age(yrs)] x [actual weight (kg)] / [72 x serum creatinine (mg/dl)] Note:
Multiply by a factor of 0.85 if female

- Serum creatinine ≤ 1.5 X ULN

11. Ability to swallow oral medications

12. All women of child-bearing potential (WCBP), all sexually active male patients, and
all partners of patients must agree to use adequate methods of birth control
throughout the study. Women of child-bearing potential (defined as being less than 1
year post-menopausal) must have a negative serum or urine β human chorionic
gonadotropin (βhCG) pregnancy test; and men and women of reproductive potential must
agree to practice an effective method of avoiding pregnancy while receiving study
drug and for 30 days after the final dose of study drug. Effective contraception
includes use of oral contraceptives with an additional barrier method, double barrier
methods (diaphragm with spermicidal gel or condoms with contraceptive foam),
Depo-Provera, partner vasectomy, and total abstinence.

13. Ability to understand the nature of this study protocol and give written informed

14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.

Exclusion Criteria:

1. Any prior systemic or investigational therapy for metastatic pancreatic cancer.
Systemic therapy administered alone or in combination with radiation in the adjuvant
setting is permissible as long as it was completed > 6 months prior to the time of
study enrollment.

2. Inability to comply with study and/or follow-up procedures.

3. History of other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition
that, in the opinion of the investigator, renders the subject at high risk from
treatment complications or might affect the interpretation of the results of the

4. Presence of central nervous system or brain metastases.

5. Life expectancy < 12 weeks

6. Pregnancy (positive pregnancy test) or lactation.

7. Concurrent active malignancy. The following prior malignancies ARE allowed:
adequately treated non-melanoma skin cancer; in situ cervical cancer; localized
prostate cancer; or adequately treated Stage I or II cancer for which treatment was
completed more than one year ago and from which the patient is currently in complete
remission; or any other form of cancer from which the patient has been disease-free
for 5 years.

8. Patients with a history of stroke, unstable angina, myocardial infarction, or
ventricular arrhythmia requiring medication or mechanical control within the last 6

9. Lack of physical integrity of the upper gastrointestinal tract or malabsorption

10. Known, existing uncontrolled coagulopathy. Patients who have had a venous
thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring
anticoagulation are eligible IF: they are appropriately anticoagulated and have not
had a Grade 2 or greater bleeding episode in the 3 weeks before Day 1. However, as
concurrent/pre-existing use of coumadin is not allowed, only low-molecular heparin
should be used.

11. Pre-existing sensory neuropathy > grade 1.

12. Major surgery within 4 weeks of the start of study treatment, without complete

13. Cirrhotic liver disease, ongoing alcohol abuse, or known chronic active or acute

14. Concurrent administration of the medications or foods which are known to inhibit
CYP3A activity to a clinically relevant degree (see Appendix 1).

15. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency.

16. Known hypersensitivity reaction to a sulfonamide.

17. Presence of active infection requiring systemic use of antibiotics within 72 hours of

18. Known human immunodeficiency virus (HIV) positivity.

19. Known hypersensitivity to IPI-926 or any of the excipients in IPI-926 capsules.

20. Pregnant or lactating women.

21. Any other co-morbid condition(s) that may interfere with study participation which in
the judgment of the Investigator would place the patient at undue risk or interfere
with the study. Examples include, but are not limited to sepsis, recent significant
traumatic injury, and other conditions.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The maximum tolerated dose (MTD) for FOLFIRINOX plus IPI-926 in patients with advanced pancreatic cancer.

Outcome Time Frame:

Ongoing evaluation through sequential dose cohorts; evaluations at 2-week intervals up to one year.

Safety Issue:


Principal Investigator

Andrew Ko, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of California, San Francisco


United States: Institutional Review Board

Study ID:




Start Date:

August 2011

Completion Date:

December 2013

Related Keywords:

  • Pancreatic Cancer
  • Adenocarcinoma
  • Pancreatic Neoplasms
  • pancreas
  • cancer
  • adenocarcinoma
  • Oxaliplatin
  • Leucovorin
  • Irinotecan
  • 5-FU
  • IPI-926
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Neoplasms
  • Pancreatic Neoplasms



University of Wisconsin Comprehensive Cancer CenterMadison, Wisconsin  53792
UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470