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4 doses of AVX701 at 4e7 IU given at T=0, 3, 6, 9 weeks. Option for subjects to receive additional immunizations every 3 months after the 4th immunization if no dose-limiting toxicities or is without progressive disease

AVX701

4 doses of AVX701 at 1e8 IU given at T=0, 3, 6, 9 weeks. Option for subjects to receive additional immunizations every 3 months after the 4th immunization if no dose-limiting toxicities or is without progressive disease

4 doses of AVX701 at 4e8 IU given at T=0, 3, 6, 9 weeks. Option for subjects to receive additional immunizations every 3 months after the 4th immunization if no dose-limiting toxicities or is without progressive disease

4 doses of AVX701 given at the maximally tolerated dose at T=0, 3, 6, 9 weeks. Option for subjects to receive additional immunizations every 3 months after the 4th immunization if no dose-limiting toxicities or is without progressive disease

4 Doses of AVX701 given to Stage III colon cancer subjects at the maximally tolerated dose at T=0, 3, 6, 9 weeks. There will be no option for subjects to receive additional immunizations.

Michael Morse, M.D.

STUDY OBJECTIVES

1. The primary objective of this protocol is to determine the safety of immunization with CEA(6D) VRP in patients with advanced or metastatic CEA expressing malignancies.
2. The secondary objectives are to evaluate CEA-specific immune response to the immunizations and obtain preliminary data on response rate.

CEA represents an attractive target antigen for immunotherapy since it is over expressed in nearly all colorectal cancers and pancreatic cancers, and is also expressed by some lung and breast cancers, and uncommon tumors such as medullary thyroid cancer, but is not expressed in other cells of the body except for low-level expression in gastrointestinal epithelium \[1\]. That CEA is a potential target for T cell mediated immune responses in humans is demonstrated by the observation that CEA contains epitopes that may be recognized in an MHC restricted fashion by T cells \[2-11\]. Specifically, there is support for the existence of human cytolytic T cells (CTLs) that recognize CEA epitopes that bind to MHC molecules HLA- A2, A3, and A24. For the most part, these T cells have been generated by in vitro cultures using antigen-presenting cells pulsed with the epitope of interest to stimulate peripheral blood mononuclear cells. In addition, T cell lines have been generated after stimulation with CEA latex beads, CEA protein-pulsed plastic adherent peripheral blood mononuclear cells, or DCs sensitized with CEA RNA. T cells have also been generated from patients immunized with a vaccinia vector encoding CEA immunogen (discussed below). Using high-performance liquid chromatography mass-spectrometry-based approaches, HLA A2-presented peptides from CEA have been identified in primary gastrointestinal tumors \[12\]. Of the HLA A2 restricted epitopes of CEA, CAP-1, a nine amino acid sequence, has been shown to stimulate CTLs from cancer patients immunized with vaccinia-CEA. Cap-1(6D) is a peptide analog of CAP-1. Its sequence includes a heteroclitic (nonanchor position) mutation, resulting in an amino acid change from Asn to Asp, to enhance recognition by the T-cell receptor without any change in binding to HLA A2. Compared with the non mutated CAP-1 epitope, Cap-1(6D) has been shown to enhance the sensitization of CTLs by 100 to 1,000 times \[3, 5, 13\]. CTL lines could be elicited from peripheral blood mononuclear cells of healthy volunteers by in vitro sensitization to the Cap-1(6D) peptide but not to the CAP-1 peptide. These cell lines can lyse human tumor cells expressing endogenous CEA.

A Phase I/II Study With CEA(6D) VRP Vaccine in Patients With Advanced or Metastatic CEA-Expressing Malignancies

A Phase I/II Study of Active Immunotherapy With CEA(6D)VRP Vaccine(AVX701)in Patients With Advanced or Metastatic Malignancies Expressing CEA or Stage III Colon Cancer

Duke University

AlphaVax, Inc.

Antineoplastic Agents

Angiogenesis Inhibitors

Endothelial Growth Factors

Mitogens

Tyrosine Kinase Inhibitors

Jourik A Gietema, MD/PhD

Angiogenesis inhibitors and EGFR inhibitors not only have anti tumor activity but also modify physiological processes. This study evaluates effects on vascular function, endocrine function and metabolism. Changes in these parameters will be analysed for predictive value for treatment efficacy.

Background

In recent years, multiple new agents have been developed that inhibit angiogenesis and the epidermal growth factor receptor (EGFR) signalling pathway.

The cell signalling routes that are inhibited by these agents however are not only active in tumour formation but are also involved in physiological processes in normal tissue and organs. This means that these drugs do not only have an anti tumour effect but also modify several physiological processes that lead to side effects. Little is known about these side effects that generally are less severe than side effects of cytotoxic chemotherapy, but because targeted therapy is often administered for prolonged periods of time, these side effects can seriously affect quality of life.

Objectives

Primary objectives

1. To determine the characteristics, frequency and severity of vascular, metabolic and hormonal side effects of angiogenesis and EGFR inhibitors.

Secondary objectives

1. To investigate if steroid profile, indol profile, concentrations of catecholamines and metanephrines or thyroid antibodies change during treatment with angiogenesis and EGFR inhibitors.
2. To investigate if known biomarkers change during treatment.
3. To investigate whether vascular function changes during treatment with angiogenesis and EGFR inhibitors.
4. To determine if changes in skin autofluorescence and development of AGE's occur during treatment with angiogenesis and EGFR inhibitors.
5. To determine whether changes in factors mentioned under secondary objectives 1-4 are correlated with side effects of targeted therapy and/or response to angiogenesis and EGFR inhibitors.
6. To evaluate if polymorphisms in genes involved in pathways mentioned under 1-4 associate with toxicity and efficacy of angiogenesis and EGFR inhibitors.

Study design and population

This is a prospective, explorative observational cohort study in patients treated with angiogenesis or EGFR inhibitors. Concomitant chemotherapy, immunotherapy or radiotherapy is allowed. Patients must be 18 years or older at start of treatment and must be willing to give written informed consent.

Primary study parameters

Patients will be evaluated for vascular changes by measuring

* 24-hour ambulatory blood pressure
* nail fold capillary microscopy
* skin autofluorescence at 3 time points: before start of treatment, and after 3 and after 6 weeks of treatment. Patients will also be asked to measure their blood pressure at home twice a day, for 6 weeks. Metabolic and hormonal changes and investigation of biomarkers will be done by blood and urine analyses every 3 weeks for the first 3 months, every 6 weeks up to 6 months and every 3 months thereafter.

Changes in vascular, hormonal and metabolic status will be related to clinical side effects and to response to treatment.

Secondary study parameters

When clinically relevant differences in side effects and response to treatment are found among patients treated with the same agent, DNA analysis will be carried out to investigate if changes in candidate genes are related to these differences.

Burden and risks associated with participation, benefit and group relatedness

The minimal invasive tests will be performed during routine outpatient visits. As far as known no serious adverse events are linked to the described study procedures. With this study we hope to get insight into the characteristics, frequency, severity and underlying mechanisms of angiogenesis and EGFR inhibitor induced vascular, metabolic and hormonal side effects and to find usable surrogate markers for efficacy of treatment. Eventually, this may contribute to the early detection of vascular, metabolic and hormonal changes, to the design of intervention strategies for side effects and to better patient selection for angiogenesis and EGFR inhibition.

Side Effects of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) Directed Therapy

Mabtornib Protocol.Vascular, Metabolic and Hormonal Effects of Angiogenesis Inhibitors and Epidermal Growth Factor Receptor Inhibitors

Vascular function tests at baseline, after 3 and after 6 weeks of treatment, blood and urine measurements as long as treatment is continued.

University Medical Center Groningen

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I/II Study With CEA(6D) VRP Vaccine in Patients With Advanced or Metastatic CEA-Expressing Malignancies	NCT00529984	Colorectal Canc... Breast Cancer Lung Cancer Pancreatic Canc... Colon Cancer	AVX701 AVX701 AVX701 AVX701 AVX701	18 Years -	AlphaVax, Inc.
Side Effects of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) Directed Therapy	NCT00657098	Metastatic Mali...		18 Years -	University Medical Center Groningen
Side Effects of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) Directed Therapy	NCT00657098	Metastatic Mali...		18 Years -	University Medical Center Groningen

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