E-Newsletter - November 2019
Spotlight on Alliance Trials
 

Alliance Trial to EXPLORE vitamin d status in relation to colorectal cancer

Alliance A021703: Randomized double-blind phase III trial of vitamin D3 supplementation in patients with previously untreated metastatic colorectal cancer (SOLARIS)

This Alliance phase III trial looks at how well vitamin D3 given with standard chemotherapy and bevacizumab works in treating patients with colorectal cancer that has spread to other parts of the body.

Study Rationale
The hypothesis that vitamin D status is related to colorectal cancer (CRC) has received strong experimental support over the past two decades, based on the almost ubiquitous expression in colon cancer cells of the vitamin D receptor (VDR)and 1-α-hydroxylase (CYP27B1), which converts plasma 25(OH)D into1,25-dihyroxycholecalciferol [1,25(OH)2D], the active metabolite.[1-3] Epidemiologic data also support the vitamin D hypothesis, with multiple prospective observational studies consistently showing a significant relationship between higher plasma 25(OH)D levels and improved survival among patients with CRC.[4-7]

Given compelling preclinical and epidemiologic data, the SUNSHINE multicenter randomized, double-blind, phase II trial was conducted to address causality in the relationship between vitamin D and CRC.[8]  Based on the resulting positive data from the SUNSHINE trial, a larger confirmatory phase III trial with more robust power is warranted in order to definitively determine the role of high-dose vitamin D3 supplementation in treatment of metastatic CRC. If positive, the phase III Alliance A021703 (SOLARIS trial) will be practice-changing and will result in incorporation of high-dose vitamin D3 into first-line chemotherapy as a new standard of care. This trial will also provide investigators with an invaluable cohort of metastatic CRC patients with associated biospecimens and lifestyle questionnaires for hypothesis-generating correlative studies related to vitamin D3, inflammation, immunity, and other pathways. The results of this SOLARIS trial will address causality, unveil novel insights into vitamin D3 biology, and critically impact cancer care on a global scale given the availability of vitamin D3. In an era of expensive and often toxic anti-neoplastic drugs, vitamin D3 represents an accessible treatment option with respect to both safety and cost.

Study Outcomes
The primary and secondary objectives are described below.

Primary objective

  • To compare the progression-free survival (PFS) of patients receiving high-dose cholecalciferol (vitamin D3) in combination with standard chemotherapy (leucovorin calcium, fluorouracil, and oxaliplatin [FOLFOX] or leucovorin calcium, fluorouracil, and irinotecan hydrochloride [FOLFIRI]) and bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy and bevacizumab.

Secondary objectives

  • To compare the objective response rate (ORR) of patients receiving high-dose vitamin D3 in combination with standard chemotherapy + bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy + bevacizumab.

  • To compare the overall survival (OS) of patients receiving high-dose vitamin D3 in combination with standard chemotherapy + bevacizumab versus those receiving standard-dose vitamin D3 in combination with standard chemotherapy + bevacizumab.

  • To evaluate and compare the toxicity of adding high-dose vitamin D3 versus standard-dose vitamin D3 to chemotherapy + bevacizumab.

  • To assess the influence of diet, body mass index, physical activity, and other lifestyle habits on PFS among patients with locally advanced/metastatic colorectal cancer.

  • To evaluate the incidence of vitamin D3 deficiency in participants with previously untreated metastatic colorectal cancer.

  • To compare the efficacy of high-dose vitamin D3 versus standard-dose vitamin D3 in subgroups of patients defined by baseline plasma calcifediol (25[OH]D) levels.

  • To evaluate the prognostic effect of highest-achieved 25(OH)D levels with PFS.

Key Eligibility Criteria
Some of the eligibility criteria include:

  • Histologically confirmed locally advanced/metastatic colorectal adenocarcinoma with no planned metastasectomy

  • No mismatch repair deficiency (dMMR) or high-frequency microsatellite instability (MSI-H) disease

  • Measurable disease per RECIST v1.1

  • No prior systemic treatment for metastatic disease

  • Prior neoadjuvant or adjuvant chemotherapy/radiation allowed if completed more than 12 months prior to colorectal cancer recurrence

  • Prior rectal chemoradiation permitted if radiotherapy was to less than 25% of bone marrow and completed ≥4 weeks prior to registration

  • No continuous daily vitamin D more than2,000 IU/day for the 12 months prior to registration

  • Major surgery/open biopsy completed more than 4 weeks and/or minor surgery/core biopsy completed more than 1 weeks prior to registration.

  • Not pregnant and not nursing. Women of childbearing potential must have negative pregnancy test less than 14 days prior to registration

  • Age 18 years and older

  • Eastern Cooperative Oncology Group (ECOG) performance status: 0-1.

Description of Treatment

Patients are randomized into one of two groups. Those in Group 1 will receive bevacizumab intravenously over 30-90 minutes on day 1 and oxaliplatin IV over two hours on day 1, leucovorin calcium IV over two hours on day 1, and fluorouracil IV on days 1-3 or irinotecan hydrochloride IV on day 1, leucovorin calcium IV over 90 minutes on day 1, and fluorouracil IV on days 1-3. Patients also receive high-dose cholecalciferol orally once daily on days 1-14. Cycles repeat every 14 days for five years in the absence of disease progression or unacceptable toxicity.

Those in Group 2 will receive bevacizumab and chemotherapy as in Group 1. Patients also receive standard-dose cholecalciferol orally once daily on days 1-14. Cycles repeat every 14 days for five years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every six months for five years.

Refer to the study protocol, which can be found on the Alliance website at www.AllianceNCTN.org, for complete information on the trial design, treatment plan and patient eligibility.

Study Chair: Kimmie Ng, MD, Dana-Farber Cancer Institute
E-mail: kng4@partners.org
Activated: 9/30/19
ClinicalTrials.gov Identifier: NCT04094688

References

  1. Meggouh, F., P. Lointier, and S. Saez, Sex steroid and 1,25-dihydroxyvitamin D3 receptors in human colorectal adenocarcinoma and normal mucosa. Cancer Res, 1991. 51(4): p. 1227-33.

  2. Vandewalle, B., et al., 1,25-dihydroxyvitamin D3 receptors in normal andmalignant human colorectal tissues. Cancer Lett, 1994. 86(1): p. 67-73.

  3. Zehnder, D., et al., Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab, 2001. 86(2): p. 888-94.

  4. Ng, K., et al., Circulating 25-hydroxyvitamin d levels and survival in patients with colorectal cancer. J Clin Oncol, 2008. 26(18): p. 2984-91.

  5. Mezawa, H., et al., Serum vitamin D levels and survival of patients with colorectal cancer: post-hoc analysis of a prospective cohort study. BMC Cancer, 2010. 10: p. 347.

  6. Fedirko, V., et al., Prediagnostic 25-hydroxyvitamin D, VDR and CASR polymorphisms, and survival in patients with colorectal cancer in western European ppulations. Cancer Epidemiol Biomarkers Prev, 2012. 21(4): p. 582-93.

  7. Zgaga, L., et al., Plasma vitamin D concentration influences survival outcome after a diagnosis of colorectal cancer. J Clin Oncol, 2014. 32(23): p. 2430-9.

  8. Ng, K., et al., SUNSHINE: Randomized double-blind phase II trial of vitamin D supplementation in patients with previously untreated metastatic colorectal cancer. Journal of Clinical Oncology, 2017. 35(15_suppl): p. 3506-3506.

 

For other articles in this issue of the Alliance E-News newsletter, see below.