Gemcitabine and Pulse Dose Erlotinib in Second Line Treatment of Advanced Pancreatic Cancer
| Status: | Recruiting |
|---|---|
| Conditions: | Cancer, Cancer, Pancreatic Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | July 2013 |
| End Date: | May 2017 |
| Contact: | Nina Rae Hintlian |
| Email: | nrhintlian@ucsd.edu |
| Phone: | 858-822-5363 |
A Phase I, Open-label, Dose Escalation Study of Gemcitabine and Pulse Dose Erlotinib in Second Line Treatment of Advanced Pancreatic Cancer
The purpose of this study is to see whether an altered schedule of giving erlotinib in
combination with gemcitabine will be safe and might improve the results of the treatment for
advanced cancer of the pancreas.
Gemcitabine and erlotinib are commercially available. Gemcitabine is FDA approved as
first-line treatment for patients with locally advanced, unresectable or metastatic cancer
of the pancreas. Erlotinib is FDA approved in combination with gemcitabine for the
first-line treatment of patients with locally advanced, unresectable or metastatic
pancreatic cancer.
The FDA recommended dose for erlotinib is 100 mg daily. This study will investigate the
experimental administration of higher doses of erlotinib given for only three days twice a
month, a schedule called "pulse dosing".
combination with gemcitabine will be safe and might improve the results of the treatment for
advanced cancer of the pancreas.
Gemcitabine and erlotinib are commercially available. Gemcitabine is FDA approved as
first-line treatment for patients with locally advanced, unresectable or metastatic cancer
of the pancreas. Erlotinib is FDA approved in combination with gemcitabine for the
first-line treatment of patients with locally advanced, unresectable or metastatic
pancreatic cancer.
The FDA recommended dose for erlotinib is 100 mg daily. This study will investigate the
experimental administration of higher doses of erlotinib given for only three days twice a
month, a schedule called "pulse dosing".
Survival of pancreatic cancer patients remains poor, and treatment with erlotinib remains
one of the few agents that have demonstrated increased survival. Alternative dosing
schedules for erlotinib should be explored since chronic low dose therapy fails to achieve
therapeutically effective concentrations for many patients and leads to increased skin
toxicity and may induce acquired resistance without significantly impacting the tumor.
Therefore, higher doses given for shorter periods of exposure, similar to the dosing of most
chemotherapeutic agents, may achieve more effective therapeutic doses of than chronic low
dose therapy and may minimize skin toxicity observed with erlotinib.
No phase I studies have been done with the combination of high dose pulse erlotinib therapy
with gemcitabine. We propose a phase I dose escalation study of three day oral dosing of
erlotinib with standard dose (1000 mg/m2) gemcitabine. The starting dose of erlotinib is 750
mg, approximately 50% of the the dose found to be safe in previous combination studies with
carboplatin and paclitaxel and with pemetrexed [Riely et al. 2009, Davies et al. 2009].
Since acquired resistance can occur rapidly and 5 to 7 days of treatment is not better than
3 days of treatment, we will focus on a 3 day high-dose pulse treatment given every 14 days.
This will provide 11 days between erlotinib dosing for the recovery of normal tissues.
Levels of serum erlotinib will also be monitored due to considerable interpatient
variability in the metabolism of erlotinib.
The hypotheses of this study are:
- High-dose pulse therapy with erlotinib can be safely administered with standard dose
gemcitabine.
- High-dose pulse therapy with erlotinib will permit recovery of the epidermis between
treatments resulting in reduced skin toxicity compared to chronic daily dosing.
- Disease control with high-dose pulse therapy may be superior to that with chronic low
dose therapy.
one of the few agents that have demonstrated increased survival. Alternative dosing
schedules for erlotinib should be explored since chronic low dose therapy fails to achieve
therapeutically effective concentrations for many patients and leads to increased skin
toxicity and may induce acquired resistance without significantly impacting the tumor.
Therefore, higher doses given for shorter periods of exposure, similar to the dosing of most
chemotherapeutic agents, may achieve more effective therapeutic doses of than chronic low
dose therapy and may minimize skin toxicity observed with erlotinib.
No phase I studies have been done with the combination of high dose pulse erlotinib therapy
with gemcitabine. We propose a phase I dose escalation study of three day oral dosing of
erlotinib with standard dose (1000 mg/m2) gemcitabine. The starting dose of erlotinib is 750
mg, approximately 50% of the the dose found to be safe in previous combination studies with
carboplatin and paclitaxel and with pemetrexed [Riely et al. 2009, Davies et al. 2009].
Since acquired resistance can occur rapidly and 5 to 7 days of treatment is not better than
3 days of treatment, we will focus on a 3 day high-dose pulse treatment given every 14 days.
This will provide 11 days between erlotinib dosing for the recovery of normal tissues.
Levels of serum erlotinib will also be monitored due to considerable interpatient
variability in the metabolism of erlotinib.
The hypotheses of this study are:
- High-dose pulse therapy with erlotinib can be safely administered with standard dose
gemcitabine.
- High-dose pulse therapy with erlotinib will permit recovery of the epidermis between
treatments resulting in reduced skin toxicity compared to chronic daily dosing.
- Disease control with high-dose pulse therapy may be superior to that with chronic low
dose therapy.
Inclusion Criteria:
- Pathologically confirmed advanced pancreatic cancer defined as non-operable in a
curative intent, locally recurrent, or metastatic disease.
- Measureable disease by (Response Evaluation Criteria in Solid Tumors) RECIST v1.1.
Measureable lesions will be confirmed by radiological imaging.
- Progressive disease by (Response Evaluation Criteria in Solid Tumors) RECIST criteria
during or after treatment with first-line chemotherapy (disease free interval must be
less than 6 months) and have not received further second-line chemotherapy. Patients
treated with prior chemo-radiation to the primary pancreatic tumor, for which the
chemotherapeutic agent was used as a radio-sensitizing agent, are eligible.
- Age >18 years.
- Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 0-2.
- Life expectancy of >2 months.
- Adequate laboratory parameters: All tests to be performed within 5 days prior to the
first dose of erlotinib
- Women of child-bearing potential and men with partners of child-bearing potential
must agree to use adequate contraception prior to study entry, for the duration of
study participation, and for 90 days following completion of therapy.
- Women of child bearing potential must have a negative pregnancy test at screening.
Exclusion Criteria:
- Radiation within 4 weeks of study enrollment. Radiotherapy not permitted while on
study. Exception: palliative radiotherapy of metastasis in extremities is allowed,
but such lesions cannot be used as target or non-target lesions.
- Investigational compound within 4 weeks of enrollment or who are planning to receive
other investigational drugs while participating in the study.
- Chemotherapy, biologics, immunotherapy, vaccine, cytokine therapy within 4 weeks
prior to enrollment.
- Presence of untreated and/or symptomatic central nervous system (CNS) metastasis.
- Severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, congestive
heart failure, myocardial infarction within 6 months of study, chronic renal disease,
chronic pulmonary disease or active uncontrolled infection).
- Known diagnosis of human immunodeficiency virus (HIV) infection.
- Presence of any other active or suspected acute or chronic uncontrolled infection or
known symptomatic active hepatitis B or C.
- Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or unstable
cardiac or coronary artery disease.
- History of another malignancy within 5 years prior to study entry, except curatively
treated non-melanotic skin cancer, cervical cancer in situ, localized biopsy-proven
prostate cancer, or stage I colon cancer.
- Surgery within 3 weeks prior to enrollment.
- Patients taking Coumadin® or other agents containing warfarin, rivaroxaban, or
dabigatran (exception: low dose Coumadin® (1 mg or less daily) administered
prophylactically for maintenance of in-dwelling lines or ports is allowed).
- Patients taking any medications or substances that are inhibitors or inducers of
Cytochrome P450, family 3, subfamily A (CYP3A).
- Female patients who are pregnant or breast-feeding.
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