Open-Label Phase 2 Efficacy Trial of Cancer Macrobeads in Patients With Treatment-Resistant Pancreatic/Colorectal Cancer

This is a clinical research study of an investigational (FDA BB-IND 10091) treatment for patients with pancreatic cancer (all stages) and advanced colorectal cancer that no longer responds to standard therapies.

The treatment is being evaluated for its effect on tumor growth. It consists of the placement (implantation) of small beads that contain mouse renal adenocarcinoma cells (RENCA macrobeads). The cells in the macrobeads produce substances that have been shown to slow or stop the growth of tumors in experimental animals and veterinary patients. It has been tested in 31 human subjects with different types of cancers in a Phase I safety trial. Phase II studies in patients with colorectal, pancreatic or prostate cancers are in progress.

This is an open-label Phase 2 clinical trial. The study will have a duration of 12 months and involve a potential total of four macrobead implants for each enrolled patient, with the implants being no less than three months apart.

The RENCA macrobeads are implanted intraperitoneally, using laparoscopic surgical procedures. The macrobeads remain permanently within the peritoneal cavity, even if patients withdraw from the study and/or begin new therapy (e.g. chemotherapy). After the formal phase of the trial is completed, subjects will be followed for life.

The intent of this Phase 2 trial is to assess efficacy, safety, and tolerability of RENCA macrobeads. Screening occurs within 28 days prior to first implantation. Enrolled patients are treated with a dose of 8 RENCA macrobeads per kilogram of body weight and observed for a minimum of 3 months prior to the next implantation. A maximum of 4 implantation procedures is possible. Day 0 is the day of implantation.

Prior to the start of the study, the Investigators ensured that the protocol and any attendant documentation were approved, in writing, by the Institutional Review Board. The study was conducted in compliance with the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines (E6 \[R1\]) for conducting, recording, and reporting studies, as well as for archiving essential documents.

The Investigators, the Medical Monitor of the sponsor, and the Data Safety Monitoring Board were responsible for monitoring safety parameters collected in the study. They, collectively, provided oversight and monitoring of the safety of the participants in the study.

Eligibility Criteria:
Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the pancreas, colon or rectum.
* Radiographic evidence of metastatic cancer of the colon or rectum.
* Pancreatic cancer that is unresectable or already metastatic, or colorectal cancer that has failed available approved treatment modalities.
* For pancreatic cancer patients, prior chemotherapy is not required; for colon and rectal cancer patients must have failed available chemotherapy/targeted regimens. There were no limits to the number of prior chemotherapeutic regimens.
* The patient had evidence of progressive disease defined as at least one of the following:

  1. Progressive measurable disease using conventional solid tumor criteria.
  2. Increasing tumor markers and/or activity on positron emission tomography / standard uptake value (PET/SUV) measurement.
* All clinically significant toxic effects (excluding alopecia) of prior surgery, radiotherapy, or hormonal therapy were resolved to ≤ Grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v.3.0) with the exception of neuropathy, which was resolved to ≤ Grade 2.
* Performance status (ECOG PS) 0-2.
* Adequate hematologic function, minimum requirements:

  1. absolute neutrophil count (ANC) ≥ 1500/mL
  2. hemoglobin ≥ 9 g/dL
  3. platelets ≥ 100,000/mL
* Adequate hepatic function, defined as follows:

  1. bilirubin ≤ 1.5 times the upper limit of normal (ULN)
  2. aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times the ULN, or ≤ 5 times the ULN if liver metastases are present
* Adequate renal function, defined as serum creatinine ≤ 2.0 mg/dL.
* Adequate coagulation function, defined as follows:

  1. an international normalized ratio (INR) ≤ 1.5
  2. a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN, unless on anti-coagulant therapy
  3. patients receiving full-dose anticoagulation therapy were eligible provided they met all other criteria, were on a stable dose or anticoagulant therapy or low molecular weight heparin (and if on warfarin had a therapeutic INR between 2-3)
* Life expectancy of at least 6 weeks.
* For females of childbearing potential, a negative pregnancy test.
* Agrees to contraceptive use (barrier method) while on study, if sexually active.
* Provided signed informed consent.

Exclusion Criteria:

* Any condition presenting an unacceptably high anesthetic or surgical risk, based on current anesthesia/general surgery standards.
* Positive test for HIV, hepatitis B, C, or E.
* Cognitive impairment such as to preclude informed consent.
* Hypersensitivity reaction that, in the opinion of the investigators posed an increased risk of an allergy to the macrobeads, particularly any known allergy to murine antigens or body tissues.
* Surgical treatment or chemotherapy within three weeks of scheduled macrobead implantation or within four weeks of bevacizumab (or similar drugs), or radiation therapy within four weeks of scheduled macrobead implantation.
* Investigational medication(s)/therapies for respective tumor within one month of baseline evaluation.
* Inadequate hematologic function, defined as follows:

  1. ANC \< 1500/mL
  2. hemoglobin \< 9 g/dL
  3. platelets \< 100,000/mL
* Inadequate hepatic function, defined as follows:

  1. bilirubin \> 1.5 times the ULN
  2. AST and ALT \> 3 times the ULN or \> 5 times the ULN, if liver metastases present
* Inadequate renal function, defined as serum creatinine \> 2.0 mg/dL.
* Inadequate coagulation function, defined as follows:

  1. INR \> 1.5
  2. PTT \> 5 seconds (unless on anti-coagulant therapy)
* Hepatic blood flow abnormalities, portal vein hypertension and thrombosis, and/or large-volume ascites.
* Concurrent cancer of any other type except skin cancer (excluding melanoma).
* Ongoing or active infection, congestive heart failure, unstable angina, serious cardiac arrhythmias, psychiatric illness, difficult social situations not permitting reliable participation, active bleeding.
* As a result of the medical history, examination, or blood testing, the investigator considers the patient unfit for the study.