Role of Antisecretory Factor in Dihydropyrimidine Treatment of Colorectal Cancer

Study Overview
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Brief Summary
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One debilitating, and sometimes even life-threatening, toxicity from dihydropyrimidines, e g 5-FU and capecitabine, is gastrointestinal mucositis resulting in, eg severe diarrhoea necessitating in-hospital care including periods of support with iv fluids. The efficacy of current treatment for this adverse effect include iv fluids, loperamide and opioids po and octreotide sc is moderate and new treatment principles or, preferably, ways to prevent such toxicity, are urgently needed. Cholera induced diarrhoea, as well as other forms of diarrhoea-inducing agents, has been shown to elicit a stimulated, endogenous production of a protein, named antisecretory factor, ASF. ASF acts by modulating secretion of water and ions but also counteracts inflammatory processes. ASF is also produced by hens fed on a diet of fermented grains or a specific diet of sugars and amino acids, leading to an accumulation of the ASF protein in the egg yolk. Spray dried yolk in the form of a powder is commercialized as Salovum registered by the EU authorities as Food for specific medical purposes. Another way to increase ASF and, thus, to achieve benefit, is to induce its production/ conversion by ingestion of oat flakes, specially processed (similar to malting) to contain the proper mix of sugars and amino acids. Such flakes are also commercially available (SPC-flakes) as Food for specific medical purposes. Salovum has been shown to rapidly, ie within hours to a few days, antagonize diarrhoeal diseases of various etiologies. It has also been used against high fluid passages and inflammation in Crohns disease, Colitis ulcerosa and carcinoids in adults. SPC-flakes have similar effects but need weeks of administration to emerge. Interestingly from an oncological perspective, provision of exogenous ASF and induction of endogenous ASF has been shown to reduce interstitial fluid pressure (IFP) in tumours, increase tumour uptake of cytotoxic drugs and improve survival in animal tumour models. With this background the present study will investigate if administration of ASF in the form of Salovum combined with induction of endogenous ASF by intake of SPC-flakes might be beneficial in colorectal cancer (CRC) patients to prevent dihydropyrimidine based chemotherapy induced gastrointestinal mucositis and to reduce tumor interstitial fluid pressure .

Detailed Description
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The pyrimidine analogue 5-fluorouracil (5-FU) has a history in oncology for more than 50 years, and is still the backbone in chemotherapy regimens, in particular for gastrointestinal cancer although it is now often substituted with the oral prodrug capecitabine. Since colorectal cancer is the third most common cancer in Europe and the US a great number of patients will be exposed to 5-FU either as part of a curative intent, ie (neo)adjuvant, or with a palliative intention. One debilitating, and sometimes even life-threatening, toxicity from dihydropyrimidines, e g 5-FU and capecitabine, is gastrointestinal mucositis resulting in, eg severe diarrhoea necessitating in-hospital care including periods of support with iv fluids. The efficacy of current treatment for this adverse effect include iv fluids, loperamide and opioids po and octreotide sc is moderate and new treatment principles or, preferably, ways to prevent such toxicity, are urgently needed. Mucositis is a common adverse effect also from a number of other cancer drugs as well as from radiotherapy. Cholera induced diarrhoea, as well as other forms of diarrhoea-inducing agents, has been shown to elicit a stimulated, endogenous production of a protein, named antisecretory factor, ASF. This protein has been chemically characterized in detail. ASF acts by modulating secretion of water and ions but also counteracts inflammatory processes. One of the biologically active peptides of the ASF protein is AF 16, a 16 amino acids long peptide which can easily be synthesized, is chemically very stable, and is therefore used for experimental purposes. ASF is also produced by hens fed on a diet of fermented grains or a specific diet of sugars and amino acids, leading to an accumulation of the ASF protein in the egg yolk. Spray dried yolk in the form of a powder is commercialized as Salovum registered by the EU authorities as Food for specific medical purposes, i e is not a drug from a regulatory perspective. Therefore, clinical studies with Salovum (or SPC-flakes, see below) do not need approval from the Medical Products Agency. Salovum rapidly increase the plasma ASF-concentration. Another way to increase ASF and, thus, to achieve benefit, is to induce its production/conversion by ingestion of oat flakes, specially processed (similar to malting) to contain the proper mix of sugars and amino acids. Such flakes are also commercially available (SPC-flakes) as Food for specific medical purposes and has been recommended or considered for a number of secretory pathological conditions, e g for treatment of Mb Meniére. Salovum has been shown to rapidly, ie within hours to a few days, antagonize diarrhoeal diseases of various etiologies. It has also been used against high fluid passages and inflammation in Crohns disease, Colitis ulcerosa and carcinoids in adults. SPC-flakes have similar effects but need weeks of administration to emerge. Importantly, to raise body ASF, by Salovum or SPC-flakes, for the above indications has not been associated with adverse effects. Interestingly from an oncological perspective, provision of exogenous ASF and induction of endogenous ASF has been shown to reduce interstitial fluid pressure (IFP) in tumours, increase tumour uptake of cytotoxic drugs and improve survival in animal tumour models. Thus, to raise body ASF by administration of ASF in the form of Salovum or its endogenous induction by SPC-flakes is seemingly a promising strategy worthwhile to investigate in cancer, both for treatment and counteraction of adverse effects, notably gastrointestinal mucositis, and for improvement of drug cancer treatment. While a clinical trial on administration of ASF as a strategy to improve cancer therapy, notably in glioblastoma, is in a pilot early phase, there is no study ongoing with the aim to counteract chemotherapy induced mucositis. With this background the present study will investigate if administration of ASF in the form of Salovum combined with induction of endogenous AF by intake of SPC-flakes might be beneficial in colorectal cancer (CRC) patients to prevent dihydropyrimidine based chemotherapy induced gastrointestinal mucositis. Since the study team has also experience from measurements in patients of tumour IFP using 15O-labeled water PET, a pharmacodynamic pilot study for assessement of Salovum/SPC induced changes in tumour IFP will be included as an add on to the main study and open for 10 patients with liver metastatic disease.

Official Title
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A Randomized Phase 2 and Pilot Pharmacodynamic Trial Investigating the Effect of Salovum™ and SPC-flakes on Dihydropyrimidine Induced Gastrointestinal Toxicity and Tumour Perfusion in Colorectal Cancer

Conditions
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Dihydropyrimidine Induced Gastrointestinal Toxicity in Colorectal Cancer

Intervention / Treatment
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* Dietary Supplement: Salovum and SPC-flakes active or placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. Histologically confirmed diagnosis of colorectal cancer. Planned to start 1st line dihydropyrimidine (i e 5-FU or capecitabine) based chemotherapy in the adjuvant, neoadjuvant or palliative setting. Planned duration of chemotherapy ≥ 2 months. Signed informed consent. Liver metastatic disease (pharmacodynamics study only). Exclusion Criteria: Contraindications to the investigational product, e g known or suspected hypersensitivity to the investigational products or expected inability to their use in accordance with the protocol. Lack of suitability for participation in the study, e g expected difficulties to follow the protocol procedures, as judged by the investigator. Prior exposure to 5-FU based chemotherapy. Prior exposure to Salovum or SPC-flakes.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel 2 group randomized trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>Salovum egg powder high in antisecretory factor, 4 g/sachet. Four sachets, ie 16 g q 8 h for 6 days starting 6 days before 1st cycle of chemotherapy. SPC-flakes flat dose of 75 g/d divided in 2 - 4 doses started in parallel with Salovum to be continued during the first 8 weeks of chemotherapy. | Dietary Supplement: Salovum and SPC-flakes active or placebo<br>* Foods for specific medical purposes or corresponding placebo<br>|
| Placebo Comparator: Control<br>Salovum placebo powder without antisecretory factor, 4 g/sachet. Four sachets, ie 16 g q 8 h for 6 days starting 6 days before 1st cycle of chemotherapy. SPC placebo flakes flat dose of 75 g/d divided in 2 - 4 doses started in parallel with Salovum placebo to be continued during the first 8 weeks of chemotherapy. | Dietary Supplement: Salovum and SPC-flakes active or placebo<br>* Foods for specific medical purposes or corresponding placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of diarrhoea CTCAEv5.0 ≥ grade 2. | Chemotherapy induced toxicity to be counteracted by intervention | During first 2 months of chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of in-patient care for chemotherapy induced gastrointestinal mucositis including number of days in hospital and with parenteral fluids. | Chemotherapy induced toxicity to be counteracted by intervention | During first 2 months of chemotherapy | 
| Change from baseline in patient reported hQoL and abdominal symptoms assessed by EORTC QLQ-30 and the colorectal cancer specific Q29 subscale. | Patient reported chemotherapy induced toxicity to be counteracted by intervention | During first 2 months of chemotherapy | 
| Incidence and severity of other chemotherapy induced adverse effects according to CTCAEv5.0. | Chemotherapy induced toxicity to be counteracted by intervention | During first 2 months of chemotherapy | 
| Increase in P-ASF concentration from baseline to day 7 from start of investigational product/placebo and just prior to treatment cycle 2, 3 and 4 (as applicable). | To reflect study products pharmacodynamics and patient compliance | During first 2 months of chemotherapy | 
| Relationships between P-ASF concentration and adverse effects. | Assessment of biomarker related to potential benefit | During first 2 months of chemotherapy | 
| Tumour response rate according to RECIST v1.1 (locally advanced and metastatic settings only). | Assessment of benefit, if any, from ASF elevation on drug efficacy | At 1st radiological tumor response evaluation, approximately 2 months from start of chemotherapy | 
| Incidence of adverse events CTCAEv5.0 grade ≥ 3 considered probably related to investigational products/placebo. | Assessment of study product safety when combined with chemotherapy | During first 2 months of chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dihydropyrimidine, Diarrhoea, Colorectal cancer, Antisecretory factor