Randomized Double-Blind Phase III Trial of Vitamin D3 Supplementation in Patients With Previously Untreated Metastatic Colorectal Cancer (SOLARIS)
Phase: PHASE3
Conditions: Colorectal Adenocarcinoma
Sponsor: Alliance for Clinical Trials in Oncology

 
Alliance for Clinical Trials in Oncology- Chicago Office  
125 South Wacker Suite 1600 
Chicago, IL. 60606 
P: 773-702-3541 
F: 312-345-0117 
allianceforclinicalrialsinoncology.org  
 
1 
 
September 20, 2022 
 
 
 
 
 
 
 
 
 
 
 
  
On September 15, 2022, the NCI Adult CIRB - Late Phase Emphasis reviewed A021703 (Version Date 
08/09/22), and granted approval pending modification. The CIRB determined that the regulatory and 
CIRB SOP requirements for approval are met, but the CIRB requests minor, directed modifications. Our 
response to the CIRB’s review letter received on September 16, 2022, is provided below in bold. 
Thank you for your review. Please let us know what further information we may provide. 
 
Sincerely, 
 
  
 
 
 
 
 
 
 
 
 
 

2 
 
Stipulation(s): 
A response to the following is required: 
 
Consent Form(s): 
 
1. Page 15, under “Who will see my medical information?”, under the heading “Alliance 
for Clinical Trials in Oncology and Alliance Data Innovation Lab”, the description of the 
ICAREdata® project is incomplete. In keeping with protocol section 6.1.4, the 
participant needs to be informed that the project will only occur at “selected sites” and 
the participant should be encouraged “to ask their study team if the ICAREdata® 
project applies to them”.  The current language suggests all participants at any site will 
be involved with the ICAREdata® project neither of which is true. Revise appropriately.  
 
RESPONSE: The following information has been added to the first paragraph of the 
ICAREdata language under “Who will see my medical information?”  “This project will 
only occur at selected sites. Please ask your study team if the ICAREdata® project applies 
to you.”  
 
 

 
Alliance for Clinical Trials in Oncology- Chicago Office  
125 South Wacker Suite 1600 
Chicago, IL. 60606 
P: 773-702-3541 
F: 312-345-0117 
allianceforclinicalrialsinoncology.org  
 
1 
 
August 9, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On July 21, 2022, we received a disapproval Letter for Amendment #03 of NCI Protocol 
#A021703 “Randomized Double-Blind Phase III Trial of Vitamin D3 Supplementation in Patients 
with Previously Untreated Metastatic Colorectal Cancer (SOLARIS).” Please see the attached 
response memo and revised protocol submission. The study team’s responses to each review item 
are included in bold text, with hyperlinks to each section of the protocol containing each revision. 
 
Please let us know what further information we may provide. 
 
Sincerely, 
 
 
 
 
 
  
 
 
 

2 
 
I. Comments Requiring a Response – Major Issues: 
 
# 
Section 
Comments 
1. 
Global - 
Protocol 
Will the previously funding authorized for drug distribution within the Alliance 
grant be adequate to support distribution for the increase in sample size?  If not, 
please provide the estimated amount required to support drug distribution for 
the additional sample size. 
PI Response: We have received approval from Alliance Foundation to cover 
additional drug storage/distribution for the increased sample size. 
2. 
8.1.12 
Presently reads “Participants who undergo interventional therapy for metastases 
(e.g., surgical resection, radiofrequency ablation, transarterial embolization) will 
do so according to standard institutional practice. For participants for whom an 
elective surgery or procedure is contemplated, the Study Chair should be 
notified via email prior to any planned intervention. Participants may be 
allowed to continue on study post-intervention if protocol therapy has been held 
for ≤ 28 days, if they continue to have measurable disease per RECIST v1.1 
outside of the treated metastatic lesion(s) post-intervention, and if the 
continuation of protocol therapy has been discussed with the Study Chair” 
This paragraph needs to state that all patients regardless of whether they have 
measurable disease post intervention will continue on study.  However, the 
continued use of systemic therapy may differ between those with and without 
disease by imaging and this should be described per the study team’s wish. 
PI Response: We would like to clarify that this paragraph is referring to 
continuing on protocol therapy with chemotherapy + bevacizumab + vitamin 
D3 (as opposed to continuing “on study” as currently written) post-intervention. 
We agree with the Reviewer that all patients should remain on study post-
intervention. We have now clarified this in the protocol. 
3. 
13.2.1 
The statistics section has been amended to indicate that “Patients who receive 
surgery with curative intent will be censored for PFS at the date of surgery. The 
rate of surgery with curative intent will be examined, and if the rate is 
significantly different across arms, additional sensitivity analyses may be 
carried out.”   
Given that this is a double-blinded study, it is more appropriate not to censor 
such patients at the date of surgery.  For example, if more patients go to curative 
surgery on the high dose vitamin D arm, and PFS is thereby extended on that 
arm, that should be reflected in the PFS comparison, which won’t happen if 
those patients are censored for PFS at the time of surgery.  Please remove this 
change in the censoring rule. 
PI Response:  We appreciate the feedback from the reviewer. We have 
removed the previous change in the censoring rule as suggested. Notably, we 
will add a sensitivity analysis to examine the robustness of the analysis results 

3 
 
# 
Section 
Comments 
by censoring the PFS at the surgery date. The protocol has been updated to 
reflect this change in Section 13.2.4. 
I. Recommendations: 
# 
Section 
Comments 
4. 
Global- 
Protocol 
According to our records A021703 is using TRIAD. Please confirm and 
add the following section if applicable. 
Digital Radiation Therapy Data Submission Using Transfer of Images and 
Data 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in 
clinical trials a secure method to transmit images. TRIAD anonymizes and 
validates the images as they are transferred. 
TRIAD Access Requirements: 
• A valid Cancer Therapy Evaluation Program (CTEP) Identity and 
Access Management (IAM) (CTEP-IAM) account.  
• Registration type of: Associate (A), Associate Plus (AP), Non-
Physician Investigator (NPIVR), or Investigator (IVR). Refer to the 
CTEP Registration Procedures section for instructions on how to 
request a CTEP-IAM account and complete registration in RCR. 
• TRIAD Site User role on an NCTN or ETCTN roster. 
• All individuals on the Imaging and Radiation Oncology Core provider 
roster have access to TRIAD and may submit images for credentialing 
purposes, or for enrollments to which the provider is linked in OPEN. 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need 
to install the TRIAD application on their workstation. TRIAD installation 
documentation is available at 
 
This process can be done in parallel to obtaining your CTEP-IAM account and 
RCR registration. 
For questions, contact TRIAD Technical Support staff via email 
 
PI Response:  This study does not use the Transfer of Images and Data 
(TRIAD).  

 
 
1 
 
Protocol Update #02 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
_________________________________________ 
PROTOCOL UPDATE TO ALLIANCE A021703 
_________________________________________ 
 
RANDOMIZED, DOUBLE-BLINDED PHASE III TRIAL OF VITAMIN D3 SUPPLEMENTATION IN PATIENTS 
WITH PREVIOUSLY UNTREATED METASTATIC COLORECTAL CANCER (SOLARIS) 
 
 
 
 
 
X Update: 
 
 
Status Change: 
 
 
 
 
 
X Eligibility changes 
 
 
Activation 
 
 
 
 
 
X Therapy / Dose Modifications / Study Calendar changes 
 
 
Closure 
 
 
 
 
 
X Informed Consent changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
X Scientific / Statistical Considerations changes 
 
 
Reactivation 
 
 
 
 
 
 
X Data Submission / Forms changes 
 
 
 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
 
Other:  
 
No recommended IRB level of review is provided by the Alliance since the CIRB is the IRB of 
record for this trial. 
The site has 30 days after the posting of this amendment to implement it at their site. Please 
refer to the amendment application and CIRB guidelines for further instructions. 
 
 
UPDATES TO THE PROTOCOL: 
 
Cover Page (p. 1) 
 
 
 
 
 
Study Recourses (p. 2) 
• 
Under the Expedited Adverse Event Reporting heading, the website has been updated to reflect 
current boilerplate language. 
 
CTSU Address and Contact Information (Page 3) 
• 
All text in the table has been updated with current CTSU boilerplate language. 
 
Schema 
• 
The abbreviated eligibility criteria has been updated to align with the changes made in Section 3.2. 
 

2 
 
Section 2.0 Objectives 
• 
In Section 2.2.6 “Demographic and clinicopathologic characteristics” has been added to the end of 
the sentence.  
Section 3.2 Eligibility Criteria 
• 
In the 1st paragraph of Section 3.2.1, a new 2nd sentence has been added for clarity that reads: “A 
biopsy from either the primary colonic tumor and/or a metastatic site is acceptable.” 
• 
In the third paragraph of Section 3.2.3, the word “which” has been added to the 1st sentence, and a 
new 2nd sentence has been added which reads “No washout period is required after palliative 
radiation to other sites.” 
• 
In Section 3.2.7, the units have been removed from the UPC ratio and the corresponding footnote 
has been updated for clarity. 
• 
In the 3rd paragraph of Section 3.2.8, the phrase “or controlled” has been added to the end of the 
sentence.  
• 
In Section 3.2.10, the 2nd sentence of the 1st paragraph, the phrase “at least 7 days” has been 
removed.  
Section 4.0 Patient Registration  
• Section 4.2 and Section 4.4 have been updated to reflect current CTSU boilerplate 
language. 
Section 5.0 Study Calendar 
• 
The study calendar has been updated to reflect the removal of ‘serum’ from the creatinine 
collection in order to make the requirement of this collection less restrictive.  
• 
Footnote #1 has been updated to provide clarity to the collection of the Diet and Lifestyle 
Questionnaire:  Diet and Lifestyle Questionnaire “can be” completed “within” ≤ 4 weeks “after” 
enrollment. 
• 
Footnote A has been corrected to state that a “UPC ratio” not urinalysis should be performed.  
• 
‘I.E. every 8 weeks’ has been removed from footnote C.  
Section 6.0 Data and Specimen Submission 
• 
Section 6.1.2 and Section 6.1.3 have been updated to reflect current CTSU boilerplate language. 
• 
Section 6.1.4, has been updated with new ICAREdata language. 
• 
In the third paragraph of Section 6.4, ‘of’ has been replaced with ‘after.’  
 
Section 8.1.12 Surgery/Metastasectomy 
• 
In the third sentence of the paragraph, ‘on study’ has been updated to “protocol therapy with 
chemotherapy + bevacizumab + vitamin D3.” This sentence has been revised in response to CTEP 
recommendation. 
Section 8.2.2 Dose Modifications for mFOLFOX6 and FOLFIRI 
• 
‘Irinotecan’ has been added to the second sentence of the first paragraph. 
 
Section 13.0 Statistical Considerations  
• 
In the second bullet of the first paragraph in Section 13.2.1 the word “new” has been added prior 
to anti-cancer therapy.  
• 
In the first paragraph, the second and third sentences of Section 13.2.2 have been updated to reflect 
the increase in total accrual:  Based on the results from CALGB 80405, we anticipate a PFS median 
of approximately 10 months [27]. We plan to accrue a total of “445” patients “(approximately 222” 
patients per arm) in “39” months with a minimum follow-up of “13” months to achieve 273 PFS 

3 
 
events. The length of accrual time is based on an accrual rate of “3” patients per month “for the 
first 6 months, 12 patients per month for 1 year (after the first 6 months) and 14 patients per month 
for the remaining accrual period.” This design with one interim analysis for futility only with 
O’Brien-Fleming type stopping boundary (Gamma family with parameter -4 for futility) will yield 
90% power to detect a hazard ratio of 0.70 (median PFS of 10 vs. 14.3 months) assuming 
exponential survival and using a one-sided log-rank test with type I error rate of 0.05. This sample 
size takes into account a “27.6%” drop-out rate due to patients coming off treatment for reasons 
other than disease progression (e.g. surgical resection);  
• 
A second paragraph has been added to Section 13.2.2. 
• 
In the third paragraph of Section 13.2.4, a fifth and sixth sentence have been added.  
• 
In Section 13.3.1, the sample size has been increased from 400 to ‘445.’ 
• 
In Section 13.3.2, the following two sentences have been added to further clarify the accrual 
increase: “We made the same assumption for the accrual rate for the original study design. In 
Update #03 where the sample size was increased to 445, we updated the accrual rate by using three 
different accrual periods in which the rate in each period is approximately the actual observed 
accrual rate in the study (see Section 13.2.2).” 
• 
In Section 13.3.3, the monthly accrual rate has been updated.  
• 
Section 13.4.1 has the following updates: 
o In the first bullet point “Unconfirmed” has been added to the beginning of the first sentence.   
o In the third bullet point, “Toxicity: As per NCI CTCAE v5.0, the term toxicity is defined 
as adverse events that are classified as possibly, probably, or definitely related to study 
treatment,” has been replaced with “Adverse Event.” 
o In the 5th bullet point, “Prevalence” has replaced “incidence.”  
o In the 6th bullet point, “Subgroup Analyses” has replaced “Baseline 25(OH)D”; “baseline 
demographic and clinicopathologic factors (e.g., body mass index [<25 vs 25-30 vs. ≥30 
kg/m2], presence of liver metastases [yes vs. no], RAS mutation status [wildtype vs. 
mutant]). Baseline 25(OH)D” has been added to the end of the first sentence; ‘of baseline 
25(OH)D levels’ has been removed from the 4th sentence and 6th sentences and 
“Comparison of PFS across arm in subgroups of interest while adjusting for baseline 
characteristics will also be conducted as exploratory analysis” has been added as the last 
sentence of the paragraph.  
• 
In Section 13.8, the Domestic Planned Enrollment Report table has been updated to reflect the 
increased accrual and the ethnic and racial categories lists have been removed to align with the 
current Alliance model protocol template. 
 
UPDATES TO THE MODEL CONSENT: 
 
• 
In the “What is the Purpose of this study?” section the accrual was updated from 400 to 445. 
• 
The “Who will see my medical information section?” has been updated with new ICARE data 
language. 
 
 
A replacement protocol and consent document have been issued. 
____________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 

 
Version Date: 09/20/2022 
 
 
Update #02 
 
 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
ALLIANCE A021703 
RANDOMIZED DOUBLE-BLIND PHASE III TRIAL OF VITAMIN D3 SUPPLEMENTATION IN PATIENTS WITH 
PREVIOUSLY UNTREATED METASTATIC COLORECTAL CANCER (SOLARIS)  
Industry-supplied agent(s): Vitamin D3 (NSC# 375571) 
Commercial agent(s): 5-fluorouracil (NSC# 19893); Leucovorin calcium (NSC# 3590); Oxaliplatin 
(NSC# 266046); Irinotecan (NSC# 616348); Bevacizumab (NSC# 704865) 
IND #142392; IND holder: Alliance 
 
ClinicalTrials.gov Identifier: NCT04094688 
Study Chair 
 
 
 
 
 
 
 
Community Oncology Co-Chair 
Correlative Science Co-Chair 
Imaging Co-Chair 
 
 
 
 
 
 
 
 
 
 
 
 
 
GI Committee Co-Chair 
GI Committee Co-Chair 
 
 
 
 
 
 
 
 
 
ECOG-ACRIN Champion 
NRG Champion 
SWOG Champion 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Statistician 
Secondary Statistician 
Protocol Coordinator 
Data Manager 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating NCTN Groups:  
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN / ECOG-ACRIN Cancer Research Group, 
NRG / NRG Oncology, SWOG / SWOG

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
Study Resources 
Expedited Adverse Event Reporting 
 
 Medidata Rave iMedidata portal 
  
OPEN (Oncology Patient Enrollment Network) 
  
 Biospecimen Management System 
  
 
Protocol Contacts 
A021703 Nursing Contact 
 
 
 
 
A021703 Pharmacy Liaison 
 
 
 
 
Drug Distribution Contact 
 
 
 
 
 
Alliance Biorepository 
at Washington University (WUSTL) 
 
 
 
 
 
 
IROC Ohio 
 
 
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review: 
Alliance Regulatory Inbox 
  
Questions regarding CTEP-AERS reporting: 
 Alliance Pharmacovigilance Inbox  
  
Questions regarding specimens/specimen 
submissions: 
Alliance Biorepository at WUSTL 
Questions regarding drug supply: 
McKesson Clinical Research Services 
Questions regarding drug administration: 
Pharmacy Liaison 
 
 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For data submission:  
Regulatory documentation must 
be submitted to the Cancer Trials 
Support Unit (CTSU)  via the 
Regulatory Submission Portal. 
(Sign in 
 
and select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
by phone or email: 
 
 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 regulatory 
assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
 
  
 
Contact the CTSU Help Desk 
with any OPEN related 
questions by phone or email: 
 
  
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the protocol 
for further instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website
Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
For clinical questions (i.e. patient eligibility or treatment-related) see Protocol Contacts, Page 2. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU website is located at 
 
 
 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
RANDOMIZED DOUBLE-BLIND PHASE III TRIAL OF VITAMIN D3 SUPPLEMENTATION 
IN PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC COLORECTAL CANCER 
Eligibility Criteria (see Section 3.2) 
- Histologically confirmed locally advanced/metastatic colorectal 
adenocarcinoma with no planned metastasectomy 
- No known dMMR or 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 > 12 months prior to colorectal cancer recurrence 
- Prior rectal chemoradiation permitted if completed ≥ 4 weeks prior to 
registration 
- No continuous daily vitamin D ≥ 2,000 IU/day for the 12 months prior 
to registration 
- Major surgery/open biopsy completed ≥ 4 weeks and/or minor 
surgery/core biopsy completed ≥ 1 weeks prior to registration. 
- Not pregnant and not nursing. Women of childbearing potential must 
have negative pregnancy test ≤ 14 days prior to registration 
- Age ≥ 18 years; ECOG PS: 0-1 
- No resectable metastatic disease for which potentially curative 
metastasectomy is planned 
- No “currently active” second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ 
- No history of bleeding events, bleeding diathesis, arterial thrombotic events (incl. TIA, CVA, unstable angina requiring 
intervention, or MI), or clinically significant PAD ≤ 6 months of registration 
- No history of uncontrolled CHF defined as NYHA Class III or greater 
- No history of GI perforation ≤ 12 months of registration 
- No history of malabsorption, uncontrolled vomiting or diarrhea, other GI-function-affecting disease, allergic reaction 
attributed to compounds similar to study agents 
- No uncontrolled HTN, serious or non-healing wound, ulcer, or bone fracture, or uncontrolled intercurrent illness (incl. 
psychiatric illness/social situations) 
- HIV-positivity allowed if on effective anti-retroviral therapy and undetectable HIV viral load ≤ 6 months of registration 
- No pre-existing hypercalcemia 
- No known active hyperparathyroid disease or other serious Ca2+ metabolism disturbance ≤ 5 years of registration 
- No predisposing colonic or small bowel disorders with uncontrolled symptoms; colostomy or ileostomy allowed 
- No symptomatic genitourinary stones ≤ 12 months of registration 
- Treated brain metastases allowed if post-treatment imaging shows no evidence of progression ≥ 28 days prior to registration 
- New/progressive brain metastases or LMD allowed if no immediate CNS-specific treatment required 
- No uncontrolled seizure disorders or grade ≥ 2 peripheral neuropathy, neurosensory toxicity, or neuromotor toxicity 
- Must be able to swallow oral formulations 
- Concurrent use of calcium, vitamin D, thiazide diuretics, oral corticosteroids, or other anti-cancer therapy not permitted 
 
Schema 
 
 
 
 
 
One Cycle = 14 Days 
 
Treatment is to continue until 5 years after registration or disease progression, unacceptable toxicity, or withdrawal 
of consent. Patients will be followed for survival until 5 years after registration or until death, whichever comes first. 
Please refer to the full protocol text for a complete description of the eligibility criteria and treatment plan. 
Chemotherapy, imaging, and clinical follow-up must be administered/performed at the registering institution. If the 
Group credited for enrollment is a non-Alliance Group, then other requirements from the credited Group may apply. 
Required Initial Laboratory Values: 
ANC ≥ 1500/mm3 
Platelet Count ≥ 100,000/mm3 
Hemoglobin ≥ 9 g/dL 
Creatinine ≤ 1.5 x upper limit of normal 
(ULN) or Calc. CrCl > 30 mL/min 
Calcium* ≤ 1.0 x ULN 
Total Bilirubin** ≤ 1.5 x ULN 
AST/ALT*** ≤ 2.5 x ULN 
UPC Ratio ≤ 1 
or Urine Protein ≤ 1+ **** 
* Corrected for albumin level if albumin not WNL 
** If Gilbert’s disease: direct bilirubin ≤ 1.5 x ULN 
if patient to receive FOLFIRI; direct bilirubin ≤ 
3.0 x ULN if patient to receive FOLFOX 
*** AST/ALT < 5 x ULN if liver metastases 
**** If both of these are above 1, then 24-hour 
urine must be ≤ 1 g/24 hours. 
RANDOMIZE 
High-dose Vitamin D3 Arm 
[mFOLFOX6 or FOLFIRI] + Bevacizumab + High-dose Vitamin D3 
Standard-dose Vitamin D3 Arm 
[mFOLFOX6 or FOLFIRI] + Bevacizumab + Standard-dose Vitamin D3 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
Table of Contents 
ALLIANCE A021703 ................................................................................................................................... 4 
Schema ......................................................................................................................................................... 4 
Table of Contents ........................................................................................................................................ 5 
1.0 
Background ...................................................................................................................................... 8 
1.1 Rationale for Trial Design ............................................................................................................... 8 
1.2 Trial Importance............................................................................................................................. 10 
2.0 
Objectives ...................................................................................................................................... 11 
2.1 Primary Objective .......................................................................................................................... 11 
2.2 Secondary Objectives..................................................................................................................... 11 
2.3 Other Objective .............................................................................................................................. 11 
2.4 Exploratory Objectives .................................................................................................................. 11 
3.0 
Patient Selection ............................................................................................................................ 12 
3.1 On-study Guidelines ...................................................................................................................... 12 
3.2 Eligibility Criteria .......................................................................................................................... 12 
4.0 
Patient Registration ........................................................................................................................ 15 
4.1 Investigator and Research Associate Registration with CTEP ...................................................... 15 
4.2 Cancer Trials Support Unit Site Registration Procedures .............................................................. 16 
4.3 Patient Registration Requirements ................................................................................................. 19 
4.4 Patient Registration/Randomization Procedures ............................................................................ 19 
4.5 Stratification Factors and Treatment Assignments ........................................................................ 20 
5.0 
Study Calendar ............................................................................................................................... 21 
6.0 
Data and Specimen Submission ..................................................................................................... 23 
6.1 Data Collection and Submission .................................................................................................... 23 
6.2 Specimen Collection and Submission ............................................................................................ 25 
6.3 Imaging Report Submission ........................................................................................................... 26 
6.4 Diet and Lifestyle Questionnaire Completion and Submission ..................................................... 26 
7.0 
Treatment Plan/Intervention .......................................................................................................... 27 
7.1 Chemotherapy + Bevacizumab + Vitamin D3 ............................................................................... 27 
7.2 Imaging .......................................................................................................................................... 29 
8.0 
Dose and Treatment Modifications, Unblinding ............................................................................ 30 
8.1 Ancillary Therapy, Concomitant Medications, and Supportive Care ............................................ 30 
8.2 Dose Modifications ........................................................................................................................ 32 
8.3 Unblinding Procedures................................................................................................................... 33 
9.0 
Adverse Events .............................................................................................................................. 34 
9.1 Routine Adverse Event Reporting ................................................................................................. 34 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
9.2 CTCAE Routine Reporting Requirements ..................................................................................... 35 
9.3 Expedited Adverse Event Reporting (CTEP-AERS) ..................................................................... 35 
10.0 
Drug Information ........................................................................................................................... 38 
10.1 
General Considerations.............................................................................................................. 38 
10.2 
Vitamin D3 (NSC# 375571) ...................................................................................................... 39 
10.3 
Fluorouracil (Adrucil®, 5FU, NSC# 19893) ............................................................................. 40 
10.4 
Leucovorin Calcium (NSC# 3590) ............................................................................................ 42 
10.5 
Oxaliplatin (Eloxatin®, OXAL, NSC# 266046) ....................................................................... 44 
10.6 
Irinotecan (Camptosar, NSC# 616348) ..................................................................................... 48 
10.7 
Bevacizumab (NSC# 704865) ................................................................................................... 51 
11.0 
Measurement of Effect ................................................................................................................... 53 
11.1 
Schedule of Evaluations ............................................................................................................ 53 
11.2 
Definitions of Measurable and Non-measurable Disease .......................................................... 54 
11.3 
Guidelines for Evaluation of Measurable Disease ..................................................................... 54 
11.4 
Measurement of Treatment/Intervention Effect ........................................................................ 55 
11.5 
Definitions of Analysis Variables .............................................................................................. 57 
12.0 
End of Treatment/Intervention ....................................................................................................... 58 
12.1 
Duration of Protocol Treatment ................................................................................................. 58 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention .............................................. 58 
12.3 
Follow-up .................................................................................................................................. 58 
12.4 
Extraordinary Medical Circumstances ...................................................................................... 59 
12.5 
Managing Ineligible Patients and Registered Patients Who Never Receive Protocol 
Intervention ............................................................................................................................................. 59 
13.0 
Statistical Considerations ............................................................................................................... 59 
13.1 
Study Design ............................................................................................................................. 59 
13.2 
Statistical Design and Analysis for the Primary Endpoint ........................................................ 60 
13.3 
Sample Size, Accrual Time, and Study Duration ...................................................................... 62 
13.4 
Supplementary Analysis Plans .................................................................................................. 62 
13.5 
Monitoring the Study ................................................................................................................. 63 
13.6 
Study Reporting ......................................................................................................................... 64 
13.7 
Descriptive Factors .................................................................................................................... 64 
13.8 
Inclusion of Women and Minorities .......................................................................................... 64 
14.0 
Correlative and Companion Studies .............................................................................................. 65 
14.1 
Diet and Lifestyle Questionnaire Analysis ................................................................................ 65 
14.2 
Plasma 25(OH)D Level Analysis .............................................................................................. 67 
14.3 
Biobanking for Future Correlative Science Studies .................................................................. 68 
15.0 
Monitoring Plan ............................................................................................................................. 69 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
16.0 
References ...................................................................................................................................... 70 
Appendix I 
Registration Fatigue/Uniscale Assessments...................................................................... 74 
Appendix II 
Patient Medication Diary .................................................................................................. 75 
 
 
 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
1.0 
BACKGROUND 
1.1 
Rationale for Trial Design 
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 into 1,25-dihyroxycholecalciferol [1,25(OH)2D], the active 
metabolite [1-3]. Binding of VDR by 1,25(OH)2D leads to transcriptional activation and 
repression of target genes, resulting in induction of differentiation and apoptosis, and inhibition 
of proliferation, angiogenesis, and metastatic potential [4-10]. In vitro and in vivo data have 
demonstrated growth inhibition and differentiation of colon carcinoma cell lines and xenografts 
by administration of 1,25(OH)2D, and rat models of colorectal cancer maintained on a 
1,25(OH)2D diet developed fewer tumors and metastases compared to control animals [7, 11-
15]. In Apcmin mice, treatment with vitamin D or its synthetic analogs significantly decreased 
tumor burden [16]. These anti-neoplastic actions of vitamin D and the presence of 1α-
hydroxylase and VDR in CRC cells suggest that 1,25(OH)2D3 can be synthesized locally within 
the tumor and microenvironment to yield high concentrations for autocrine and paracrine 
effects. 
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 [17-20]. The first such study 
was a prospective analysis of 304 patients with stage I-IV CRC from the Nurses’ Health Study 
(NHS) and Health Professionals Follow-Up Study (HPFS) that reported that higher plasma 
25(OH)D levels were associated with significantly improved overall survival (OS) (multivariate 
HR 0.52; 95% CI 0.29 to 0.94; P trend=0.02) [17]. In subgroup analyses, the benefit of higher 
plasma 25(OH)D seemed greater in stage III and IV patients compared to stage I and II patients 
(adjusted HR 0.40 versus 0.90, respectively, comparing extreme quartiles). This finding was 
subsequently confirmed in a larger cohort of mCRC patients enrolled in the phase III 
randomized clinical trial of first-line chemotherapy, CALGB/SWOG 80405 [21]. Among 1,043 
patients in this study with available baseline plasma 25(OH)D levels, the median 25(OH)D 
concentration was deficient at 17.2 ng/mL. Patients with higher levels of 25(OH)D had 
significantly improved OS compared to those with lower levels, with a median OS of 32.6 
months versus 24.5 months, comparing extreme quintiles (adjusted HR 0.65; 95% CI, 0.51-0.83; 
P trend = 0.001). Similarly, patients with higher plasma 25(OH)D levels had significantly 
improved PFS, with a median PFS of 12.2 months versus 10.1 months, comparing extreme 
quintiles (adjusted HR 0.79; 95% CI, 0.63-0.99; P trend=0.01). 
Given the compelling preclinical and epidemiologic data above, the SUNSHINE multicenter 
randomized, double-blind, phase II trial was conducted to address causality in the relationship 
between vitamin D and CRC [22]. From 2012-2016, 139 patients with previously untreated 
mCRC were randomized to receive standard FOLFOX + bevacizumab chemotherapy with either 
a) high-dose vitamin D3 (8,000 IU/day x 2 weeks as loading dose, followed by 4,000 IU/day as 
maintenance dose), or b) standard-dose vitamin D3 (400 IU/day) in blinded fashion. There were 
several reasons for not utilizing a true placebo, including: 1) potential unwillingness of CRC 
participants to be randomized to a vitamin D placebo, which would negatively impact accrual; 
2) known prevalence of vitamin D deficiency and insufficiency in the metastatic population; 3) 
the fact that vitamin D3 400 IU daily increases serum 25(OH)D levels by only 3-4 ng/mL; and 
4) previous research indicating a lack of benefit of multivitamin supplements (which typically 
contain 400 IU of vitamin D) on outcomes in stage III colon cancer patients [23, 24]. All of 
these reasons support using vitamin D3 400 IU/day as an active control arm. The primary 

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Update #02
 
 
 
endpoint was PFS by intent-to-treat analysis, and patients were treated until disease progression, 
unacceptable toxicity, or withdrawal of consent.  
Baseline characteristics were well-balanced between the two arms in SUNSHINE, with slightly 
more ECOG performance status 1 patients randomized to high-dose vitamin D3 (58% versus 
43%, P=0.08). Median follow-up time for the entire study population was 22.9 months at the 
time of database lock on September 1, 2018, and compliance with vitamin D3 was high, with a 
median of 98% of expected capsules taken by patients in both the high-dose and standard-dose 
vitamin D arms. The majority of patients discontinued study treatment for disease progression 
(49% receiving high-dose vitamin D3 versus 54% receiving standard-dose). Interestingly, more 
patients randomized to high-dose vitamin D3 came off study to pursue potentially curative 
surgery (17% versus 9%). The addition of high-dose vitamin D3 to chemotherapy did not result 
in added toxicity; in fact, there were fewer grade 3/4 events of diarrhea among patients receiving 
high-dose vitamin D3 compared to those receiving standard-dose vitamin D3 (1% versus 12%, 
P=0.02). In regards to the primary efficacy endpoint, the SUNSHINE trial showed that high-
dose vitamin D3 significantly prolonged PFS compared to standard-dose vitamin D3. The 
multivariable HR for progression or death was 0.64 (one-sided 95% CI, 0-0.90; P=0.02) 
comparing high-dose to low-dose vitamin D3, with a median PFS of 13.0 (95% CI, 10.1-14.7) 
vs. 11.0 months (95% CI, 9.5-14.0), respectively (stratified log rank P=0.03). Further 
adjustment for primary tumor location did not change the impact of high-dose vitamin D3 on 
PFS (HR 0.66; 95% CI, 0-0.94; P=0.02). Among 128 evaluable patients, ORR was 58% vs. 63% 
(P=0.27) and disease control rate (DCR) was 100% vs. 95% (P=0.06), comparing high-dose to 
low-dose vitamin D. OS data are not yet mature, but at the time of the data lock, median OS was 
24.3 (95% CI, 19.0-33.2) vs. 24.3 (95% CI, 20.3-32.4) months, respectively (log rank P=0.43). 
Plasma 25(OH)D levels from patients enrolled on SUNSHINE are shown in Table 1. Patients 
in both arms were vitamin D deficient at baseline: median 16.1 ng/mL for high-dose and 18.7 
ng/mL for standard-dose (P=0.30). At the time of the first restaging scan at approximately 8 
weeks, patients randomized to standard-dose vitamin D3 did not have a significant change in 
their 25(OH)D levels, whereas those receiving high-dose vitamin D3 increased their levels into 
the sufficient range, with a median of 32 ng/mL (P<0.001). Similarly, at the second restaging 
scan at approximately 16 weeks, control arm patients had no appreciable change in their 
25(OH)D levels, whereas those receiving high-dose vitamin D3 had a further small rise to 
median 35 ng/mL (P<0.001). And finally, at treatment discontinuation, plasma levels in the 
standard-dose arm again remained the same, and levels among patients in the high-dose arm 
were maintained at median 35 ng/mL (P<0.001). These data reveal several important insights: 
1) vitamin D3 at 400 IU/day is an appropriate active control arm; 2) vitamin D3 8,000 IU/day x 
2 weeks followed by 4,000 IU/day effectively raises plasma 25(OH)D levels into sufficient 
range; 3) mCRC patients are vitamin D deficient at baseline, and are not already using high-
dose vitamin D prior to study enrollment; 4) no contamination of the control arm was seen in 
SUNSHINE; and 5) the high compliance rate reported by patients on SUNSHINE is now 
confirmed by the plasma 25(OH)D data [22]. 
 
 

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Table 1 
 
HIGH-DOSE 
VITAMIN D3 
STANDARD-DOSE 
VITAMIN D3 
P 
VALUE 
TIME POINT 
No. 
Median 25(OH)D 
(25th, 75th percentile) 
ng/mL 
No. 
Median 25(OH)D 
(25th, 75th percentile) 
ng/mL 
Baseline 
63 
16.1 (10.1, 23.0) 
61 
18.7 (13.5, 22.7) 
0.30 
First Restaging 
(After 4 Cycles) 
54 
32.0 (25.7, 39.5) 
50 
18.7 (16.1, 22.5) 
<0.001 
Second Restaging 
(After 8 Cycles) 
47 
35.2 (25.0, 45.4) 
37 
18.5 (16.0, 22.6) 
<0.001 
Treatment 
Discontinuation 
43 
34.9 (24.9, 44.7) 
47 
18.7 (13.9, 23.0) 
<0.001 
Change from 
Baseline to First 
Restaging 
50 
17.6 (9.9, 25.0) 
47 
-0.5 (-2.1, 3.5) 
<0.001 
Change from 
Baseline to 
Second Restaging 
46 
17.3 (7.6, 27.8) 
34 
-0.4 (-2.3, 4.0) 
<0.001 
Change from 
Baseline to 
Treatment 
Discontinuation 
38 
21.2 (6.6, 32.6) 
43 
0.8 (-3.2, 2.3) 
<0.001 
 
1.2 
Trial Importance 
Based on the positive phase II SUNSHINE data described above, 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 SOLARIS 
phase III 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. SOLARIS will also provide investigators 
with an invaluable cohort of mCRC patients with associated biospecimens and lifestyle 
questionnaires for hypothesis-generating correlative studies related to vitamin D3, 
inflammation, immunity, and other pathways. The results of SOLARIS 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. Indeed, in an era of expensive and often toxic anti-
neoplastic drugs, vitamin D3 represents an attractive and accessible treatment option with 
respect to both safety and cost. 
 
 

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2.0 
OBJECTIVES 
2.1 
Primary Objective 
To compare the progression-free survival (PFS) of patients receiving high-dose vitamin D3 in 
combination with standard chemotherapy (FOLFOX or FOLFIRI) and bevacizumab versus 
those receiving standard-dose vitamin D3 in combination with standard chemotherapy and 
bevacizumab. 
2.2 
Secondary Objectives 
2.2.1 
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. 
2.2.2 
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. 
2.2.3 
To evaluate and compare the toxicity of adding high-dose vitamin D3 versus standard-
dose vitamin D3 to chemotherapy + bevacizumab. 
2.2.4 
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. 
2.2.5 
To evaluate the incidence of vitamin D3 deficiency in participants with previously 
untreated metastatic colorectal cancer. 
2.2.6 
To compare the efficacy of high-dose vitamin D3 versus standard-dose vitamin D3 in 
subgroups of patients defined by baseline plasma 25(OH)D levels, demographic and 
clinicopathologic characteristics. 
2.2.7 
To evaluate the prognostic effect of highest-achieved 25(OH)D levels with PFS. 
2.3 
Other Objective 
Results of the primary analysis will be examined for consistency, while taking into account the 
stratification factors and/or covariates of baseline QOL and fatigue. 
2.4 
Exploratory Objectives 
2.4.1 
To evaluate the association between germline variation in vitamin D pathway genes and 
plasma 25(OH)D levels, response to vitamin D3 supplementation, and patient outcome. 
2.4.2 
To evaluate the impact of high-dose vitamin D3 versus standard-dose vitamin D3 on the 
plasma Angiome, and how the Angiome modifies the association between vitamin D3 
supplementation and patient outcome. 
 
 

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3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate 
for this protocol: 
• 
Women and men of reproductive potential should agree to use an appropriate method 
of birth control throughout their participation in this study and for 6 months after the 
last dose of study treatment due to the teratogenic potential of the therapy utilized in this 
trial. Appropriate methods of birth control include abstinence, oral contraceptives, 
implantable hormonal contraceptives, or double barrier method (diaphragm plus 
condom). 
3.2 
Eligibility Criteria 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday one week later would 
be considered Day 7. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 
12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months). 
___ 
3.2.1 
Documentation of Disease: 
Histologically confirmed advanced/metastatic colorectal adenocarcinoma for which 
metastasectomy is not planned. A biopsy from either the primary colonic tumor and/or a 
metastatic site is acceptable. 
No known dMMR or MSI-H disease. 
___ 
3.2.2 
Measurable disease per RECIST v1.1 as defined in Section 11.0. 
___ 
3.2.3 
Prior Treatment 
No prior systemic treatment for metastatic disease. 
Patients may have received prior neoadjuvant or adjuvant chemotherapy and/or 
chemoradiation. The last course of adjuvant therapy must have been completed > 12 
months prior to colorectal cancer recurrence. 
Patients may have received prior standard rectal cancer chemoradiation, which must have 
been completed ≥ 4 weeks prior to registration. No washout period is required after 
palliative radiation to other sites. 
 

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No continuous daily use of vitamin D supplements ≥ 2,000 IU per day for the 12 months 
prior to registration. Patients may have had continuous daily use of vitamin D supplements 
≥ 2,000 IU per day if total duration < 12 months in the 12 months prior to registration. 
Patients may have had continuous daily use of vitamin D supplements < 2,000 IU per day 
for any duration prior to registration. 
Patients must have completed any major surgery or open biopsy ≥ 4 weeks prior to 
registration and must have completed any minor surgery or core biopsy ≥ 1 week prior to 
registration. (Note: insertion of a vascular access device is not considered major or minor 
surgery.) Patients must have recovered from the effects of any surgery (e.g. wound is 
healed, no active infection, no drains, etc.) prior to registration. 
___ 
3.2.4 
Not pregnant and not nursing. 
This study involves an agent that has known genotoxic, mutagenic and teratogenic effects. 
Therefore, for women of childbearing potential only, a negative serum or urine pregnancy 
test done ≤ 14 days prior to registration is required. 
___ 
3.2.5 
Age ≥ 18 years 
___ 
3.2.6 
ECOG Performance Status: 0-1 
___ 
3.2.7 
Required Initial Laboratory Values: 
• 
Absolute Neutrophil Count 
≥ 1,500/mm3 
• 
Platelet Count ≥ 100,000/mm3 
• 
Hemoglobin 
≥ 9 g/dL 
• 
Creatinine 
≤ 1.5 x upper limit of normal (ULN) 
OR 
Calc. CrCl 
> 30 mL/min 
• 
Calcium 
≤ 1.0 x ULN * 
• 
Total Bilirubin ≤ 1.5 x ULN** 
• 
AST/ALT  
≤ 2.5 x ULN *** 
• 
UPC Ratio 
≤ 1  
OR 
Urine Protein 
≤ 1+ **** 
* 
Corrected for albumin level if albumin not within institutional limits of normal 
** 
If Gilbert’s disease, use direct bilirubin instead of total bilirubin; direct bilirubin 
≤ 1.5 x ULN if patient to receive FOLFIRI; direct bilirubin ≤ 3.0 x ULN if patient 
to receive mFOLFOX6 
*** 
AST/ALT < 5 x ULN if clearly attributable to liver metastases 
**** 
If both the UPC ratio and urine protein are above 1, but 24-hour urine is ≤ 1 g/24 
hours, then the patient is eligible. 
___ 
3.2.8 
Patient History 
No resectable metastatic disease for which potentially curative metastasectomy is planned. 
No “currently active” second malignancy other than non-melanoma skin cancers or 
cervical carcinoma in situ. Patients are not considered to have a “currently active” 
malignancy if they have completed therapy and have been free of disease for ≥ 3 years. 
No significant history of bleeding events or bleeding diathesis ≤ 6 months of registration 
unless the source of bleeding has been resected or controlled. 

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No history of arterial thrombotic events, including, but not limited to, transient ischemic 
attack, cerebrovascular accident, unstable angina, angina requiring surgical or medical 
intervention, or myocardial infarction ≤ 6 months of registration. 
No history of clinically significant peripheral artery disease ≤ 6 months of registration. 
No history of uncontrolled congestive heart failure defined as NYHA Class III or greater. 
No history of gastrointestinal (GI) perforation ≤ 12 months of registration except for GI 
perforation related to a primary colorectal tumor that has since been fully resected. 
No history of malabsorption, uncontrolled vomiting or diarrhea, or any other disease 
significantly affecting GI function that could interfere with the absorption of oral agents. 
No history of allergic reaction attributed to compounds of similar chemical or biological 
composition to the study agents. 
___ 
3.2.9 
Comorbid Conditions 
No uncontrolled hypertension (defined as BP >160/90). 
No serious or non-healing wound, ulcer, or bone fracture. 
No uncontrolled intercurrent illness, including, but not limited to, psychiatric illness/social 
situations that, in the opinion of the treating physician, may increase the risks associated 
with participation or treatment on the study or may interfere with the conduct of the study 
or interpretation of the study results. 
Patients positive for HIV are eligible only if they meet all of the following: 
• 
On effective anti-retroviral therapy 
• 
Undetectable HIV viral load by standard clinical assay ≤ 6 months of registration 
No known pre-existing hypercalcemia ≤ 6 months of registration. 
No known active hyperparathyroid disease or other serious disturbance of calcium 
metabolism ≤ 5 years of registration. 
No predisposing colonic or small bowel disorders in which symptoms are uncontrolled as 
indicated by > 3 watery or soft stools daily in patients without a colostomy or ileostomy. 
Patients with a colostomy or ileostomy are allowed per treating physician discretion. 
No symptomatic genitourinary stones ≤ 12 months of registration. 
Patients with treated brain metastases are eligible if follow-up imaging after CNS-directed 
therapy shows no evidence of progression ≥ 28 days prior to registration. 
Patients with new or progressive brain metastases (active brain metastases) or 
leptomeningeal disease are eligible if the treating physician determines that immediate 
CNS-specific treatment is not required and is unlikely to be required during the first cycle 
of protocol-specified therapy after registration. 
No uncontrolled seizure disorders. 
No grade ≥ 2 peripheral neuropathy, neurosensory toxicity, or neuromotor toxicity per 
CTCAE v5.0 regardless of causality. 
Patients must be able to swallow oral formulations of the agent.  

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___ 
3.2.10 Concomitant Medications 
Concurrent use of supplemental calcium and/or vitamin D is not permitted. Patients must 
discontinue the supplement(s) prior to registration. See Section 8.1.9 for more information. 
Concurrent use of thiazide diuretics (e.g. hydrochlorothiazide) is not permitted. Patients 
must discontinue the drug(s) or switch to an alternative anti-hypertensive agent at least 7 
days prior to registration. 
Chronic concomitant treatment with oral corticosteroids, lithium, phenytoin, quinidine, 
isoniazid, and/or rifampin are not permitted. Patients must discontinue the agent(s) at least 
7 days prior to registration. Short-term use of corticosteroids as antiemetic therapy is 
acceptable; see Section 8.1.10 for more information. 
Concurrent use of other anti-cancer therapy including chemotherapy, targeted, and/or 
biological agents is not permitted; see Section 8.1 for more information. 
4.0 
PATIENT REGISTRATION 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
  
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents 

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Update #02
 
 
 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
 
  
4.2 
Cancer Trials Support Unit Site Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval   
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) to the CIRB using IRBManager to indicate their intent to open the study locally. 
The NCI CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory 

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Update #02
 
 
 
Office, 
but 
sites 
are 
required 
to 
contact 
the 
CTSU 
Regulatory 
Office 
at 
to establish site preferences for applying NCI CIRB approvals 
across their Signatory Network. Site preferences can be set at the network or protocol level. 
Questions about establishing site preferences can be addressed to the CTSU Regulatory Office 
by email or calling 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval on at least one participating 
organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
4.2.1 
Additional Requirements  
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); 
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
signatory Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Protocol-Specific Requirements for A021703 Site Registration  
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must 
be aligned to an RTI provider. To manage provider associations or to add or remove 
associated providers, access the Provider Association page from the Regulatory section on 
the CTSU members’ website at 
Sites 
must be linked to at least one Imaging and Radiation Oncology Core (IROC) provider to 
participate on trials with an RTI component. Enrolling sites are responsible for ensuring 
that the appropriate agreements and IRB approvals are in place with their RTI provider. An 
individual with a primary role on any roster is required to update provider associations, 
though all individuals at a site may view provider associations. To find who holds primary 
roles at your site, view the Person Roster Browser under the RUMS section on the CTSU 
website. 
4.2.3 
Downloading Site Registration Documents  
• 
Download the site registration forms from the protocol-specific page located on 
the CTSU members’ website. Permission to view and download this protocol and 
its supporting documents is restricted to institutions and their associated 
investigators and staff on a participating roster. To view/download site registration 

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Update #02
 
 
 
forms:  Log in to the CTSU members’ website 
using your 
CTEP-IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select Alliance, 
and protocol number A021703. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.) 
4.2.4 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately  by phone or email: 
in order to receive further instruction and 
support. 
4.2.5 
Checking Site’s Registration Status  
Site registration status may be verified on the CTSU members’ website. 
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
4.2.6 
Credentialing 
There are no credentialing requirements for this trial. 
4.2.7 
Delegation of Task Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application in the Delegation Log section on the CTSU members’ website. The Clinical 
Investigator (CI) is required to review and electronically sign the DTL prior to the site 
receiving an approved site registration status and enrolling patients to the study. To 
maintain an approved site registration status the CI must re-sign the DTL at least annually 
and when a new version of the DTL is released; and activate new task assignments 
requiring CI sign-off. Any individual at the enrolling site on a participating roster may 
initiate the site DTL. Once the DTL is submitted for CI approval, only the designated DTL 

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Administrators or the CI may update the DTL. Instructions on completing the DTL are 
available in the Help Topics button in the DTL application and include a Master Task List, 
which describes DTL task assignments, CI signature, and CTEP registration requirements. 
4.3 
Patient Registration Requirements 
Informed Consent: The patient must be aware of the neoplastic nature of his/her disease and 
willingly consent after being informed of the procedure to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current 
human protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
Patient-completed Booklet: The Diet and Lifestyle Questionnaire booklet will be sent to the 
enrolling institution at the time of each patient registration/randomization. A sample of the 
booklet can be found on the Alliance and CTSU websites as a separate document, and it is to be 
used for reference and IRB submission only. It is not to be used for patient completion. 
This study includes the use of the mandatory patient-completed measure, Diet and Lifestyle 
Questionnaire. The Diet and Lifestyle Questionnaire is available in English. Completion of the 
Diet and Lifestyle Questionnaire booklet is mandatory for all patients registered to this trial who 
are able to speak, read, and/or understand this language. 
Protected Health Information: The Diet and Lifestyle Questionnaire collected for this study 
will be sent directly to the Dana-Farber Cancer Institute. This booklet will be labeled with 
patient initials and patient study ID. 
4.4 
Patient Registration/Randomization Procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and 
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 

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Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records. 
To receive site reimbursement for specific tests and/or bio-specimen submissions, completion 
dates must be entered in the OPEN Funding screen post registration. Please refer to the protocol-
specific funding page on the CTSU members’ website for additional information. Timely entry 
of completion dates is recommended as this will trigger site reimbursement. 
Access OPEN at 
or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
For any additional questions, contact the CTSU 
Help Desk at 
   
4.5 
Stratification Factors and Treatment Assignments 
Dynamic Allocation 
After a patient is registered, they will be assigned to one of the two treatment arms (treatment 
vs. control) in a 1:1 ratio utilizing a dynamic allocation algorithm based on method by Pocock 
and Simon [25]. The goal of the algorithm is to maintain arm balance with respect to the 
following important stratification factors: 
• 
Chemotherapy Backbone: mFOLFOX6 vs. FOLFIRI 
• 
Primary Tumor Location: Right (Cecum, Ascending Colon, Hepatic Flexure, 
Transverse Colon) vs. Left (Splenic Flexure, Descending Colon, Sigmoid Colon, 
Rectosigmoid Junction, Rectum) 
• 
ECOG PS: 0 vs. 1 
In order to ensure that treatment assignment is not deterministic, a level of randomness has been 
added to the algorithm such that patients will be assigned to the arm that leads to more imbalance 
90% of the time. 
 
 

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5.0 
STUDY CALENDAR 
Pre-Study Testing Intervals: 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during 
treatment are to be followed using individual institutional guidelines and the best clinical judgment 
of the responsible physician. It is expected that patients on this study will be cared for by physicians 
experienced in the treatment and supportive care of patients on this trial.  
When calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test were done on a Monday, the Monday one week later would be considered 
Day 7. 
To be completed ≤ 14 DAYS before registration: All laboratory studies, history and physical. 
To be completed ≤ 28 DAYS before registration: Any scan of any type which is utilized for tumor 
measurement per protocol. 
 
 
Prior to 
registration* 
Day 1 of each 
cycle* 
Post-treatment 
follow up** 
PD, withdrawal, 
or removal** 
Tests & Observations 
 
 
 
 
H&P, Weight, Pulse, BP, PS 
X 
X 
X 
X 
Height 
X 
 
 
 
Adverse Event Assessment 
 
X 
X 
X 
Diet/Lifestyle Questionnaire 
X(1) 
 
 
 
Patient Medication Diary 
 
X(2) 
 
 
Registration Fatigue/ Uniscale 
Assessment 
X(3) 
 
 
 
Laboratory Studies 
 
 
 
 
CBC, Differential, Platelets 
X 
X 
 
 
CMP 
X(4) 
X(4) 
 
 
Creatinine 
X 
X 
 
 
Albumin, Glucose 
X 
X 
 
 
AST, ALT, Alkaline 
Phosphatase, Total Bilirubin 
X 
X 
 
 
Serum or Urine HCG 
X(5) 
 
 
 
UPC Ratio/Urine Protein 
X 
A 
 
 
CEA 
X 
B 
 
X 
Staging 
 
 
 
 
CT (or MRI) Chest, Abd/Pelvis 
C 
C 
C 
C 
Correlative Studies: For patients who consent to participate in A021703 Biobanking 
Blood, Tissue, and/or Stool 
Baseline, during treatment, and end of treatment; see Section 6.2. 

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* 
Labs, tests, and observations completed prior to registration may be used for Day 1 of Cycle 1 tests 
if obtained ≤ 7 days prior to treatment. For subsequent cycles, labs, tests, and observations may be 
obtained ≤ 3 days prior to day of treatment.  
** 
If protocol therapy is discontinued for reasons other than disease progression, then physical 
examination, AE assessment, and restaging scans are required every 8-16 weeks (+/- 1 week) until 
5 years from registration, disease progression, or start of new anticancer therapy, whichever comes 
first; thereafter, survival information is required every 6 months until 5 years from registration. See 
also Section 12.0.  
1 
Diet and Lifestyle Questionnaire can be completed within ≤ 4 weeks after enrollment; see Section 
4.3, Section 6.4, and Section 14.1. 
2 
The diary must begin the day the patient starts taking vitamin D3 and must be completed per 
protocol and returned to the treating institution or compliance must be documented in the medical 
record by any member of the care team. See Appendix II for a copy of the diary. 
3 
To be completed ≤ 21 days prior to treatment.  
4 
At minimum, CMP should include the following: sodium, potassium, carbon dioxide, chloride, 
BUN, calcium, magnesium, phosphorus. 
5 
For women of childbearing potential, to be done ≤ 14 days prior to registration; see Section 3.2. 
A 
All patients receiving bevacizumab should have a UPC ratio or urine protein performed every 
other cycle starting with Cycle 1; if urine protein is ≥ 2+, 24-hour urine collection or UPC ratio 
needs to be obtained. 
B 
To be obtained at baseline and then every 4 cycles thereafter (beginning prior to Cycle 5) until 5 
years from registration or until evidence of disease progression or relapse. Any measurements of 
biochemical response should occur in conjunction with the radiographic assessments for disease 
status. 
C 
Baseline scans should include a CT (or MRI) of the chest, abdomen, and pelvis performed with 
both IV and oral contrast if possible. Restaging scans will be performed every 4 cycles while on 
protocol therapy. Response assessment should include assessment of all sites of disease, and the 
same imaging method used at baseline should be used for all subsequent evaluations. Multiphase 
CT scan (chest/abdomen/pelvis) is the preferred imaging modality; equivalent modalities (MRI 
scan of the abdomen/pelvis with chest CT) may be used per treating physician discretion. CT 
scans should be of diagnostic quality and CT abdomen/pelvis performed with oral and IV contrast 
unless there is a medical contraindication. MRI scans should be of diagnostic quality and 
performed with IV contrast unless there is a medical contraindication. Scans may be obtained up 
to 7 days prior to the beginning of a new cycle. Supporting documentation is to be submitted per 
Section 6.1.5.  
 
 

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6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
6.1.1 
Data Submission Schedule 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the 
Case Report Forms section. The DSS is also available on the CTSU website within the 
study-specific Case Report Forms folder. 
6.1.2 
Medidata Rave 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and 
role assignments.  
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (Lab Admin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to 
for registration types 
and documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access 
to Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
email from iMedidata. To accept the invitation, site staff must either click on the link in 
the email or log in to iMedidata via the CTSU members’ website under Data Management 
> Rave Home and click to accept the invitation in the Tasks pane located in the upper right 
corner of the iMedidata screen. Site staff will not be able to access the study in Rave until 
all required Medidata and study specific trainings are completed. Trainings will be in the 
form of electronic learnings (eLearnings) and can be accessed by clicking on the eLearning 
link in the Tasks pane located in the upper right corner of the iMedidata screen. If an 
eLearning is required for a study and has not yet been taken, the link to the eLearning will 
appear under the study name in the Studies pane located in the center of the iMedidata 
screen; once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will replace the eLearning link.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the 
CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 

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> Rave section at 
or by contacting the CTSU Help Desk at 
  
6.1.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports 
modules are available to access details and reports of unanswered queries, delinquent 
forms, forms with current status and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP For Status, and DQP Reports modules. 
6.1.4 
ICAREdataTM 
Selected sites will be participating in the ICAREdata® project. - The Integrating Clinical 
Trials and Real-world Endpoints data (ICAREdata) initiative is a program led by the 
Alliance Data Innovation Lab which is a component of the Alliance for Clinical Trials in 
Oncology.  
The ICAREdata® project aims to expand the ability to achieve clinical research goals by 
providing new ways to collect data required for clinical trials.  Today, virtually all clinical 
trials data are collected using special forms and computer applications, such as a software 
known as Medidata Rave.  Instead of using these “add on” data collection systems, the 
ICAREdata project will gather study data directly from the Electronic Health Record 
(EHR). As with all research data collections, data collected by the ICAREdata project are 
stored in a secured repository.  
Select institutions will be invited to participate and will receive training on the specific 
ICAREdata® requirements. As with all clinical trials data management, the nature of data 
collected using the ICAREdata methods will be specific to a particular research protocol, 
and might include demographic information, diagnosis, laboratory values, physician 
assessments, and other results, such as adverse event reports.  The Data Innovation Lab 
will manage data collection, working with the IT department at these sites to configure the 
EHR to deliver mCODE (minimal common oncology data elements) data and other 
required outcome data in the form of structured ICAREdata questions. Clinicians will 
provide the study required data by answering standardized questions or data fields as part 
of their encounter visit with the subjects.  The IT departments will also work to implement 
the data transfer capability from the site EHR to the Alliance Data Innovation Lab via a 
secure/tested extraction method.  
Investigators and research staff at limited select sites that utilize the EHR research adverse 
events data collection tool will be asked to complete a brief voluntary survey. The research 
staff and investigator’s email addresses at these predetermined sites will be submitted at 
the time of Adverse Events data collection tool training.  The survey will take 
approximately 5 minutes to complete.  It will solicit feedback on the investigators and study 

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staff experiences including overall staff acceptance, usability, preferences for using the tool 
to document any adverse events. The plan survey administration timeline is at baseline and 
then a select period thereafter. Ultimately, the survey will be used to gather general 
feedback of the usability of the tool across multiple site level stakeholders. 
Data will be encrypted at-rest and in-transit using a secure interface with an established 
authorization protocol handled by the ICAREdata infrastructure. Alliance Data Lab staff 
will issue a client ID and credentials to participating ICAREdata sites that will be used to 
authenticate those sites for access to the ICAREdata infrastructure service/extraction 
method to submit data. The clinical site will be responsible for securely storing these 
credentials (e.g., installed on a server that an IT administrator manages) such that those 
staff responsible for submitting data will have the proper access. Data will be stored and 
maintained in HIPAA compliant data repositories (such as AWS) and access controlled by 
an identity server with strict management to ensure confidentiality, integrity, and 
availability of PHI. Strict access controls will be maintained. Only authorized Alliance 
Data Lab personnel will have access to the data and scope of access will be further 
controlled based on role and level of need to know. 
Participating institutions may email the Alliance Data Innovation Lab at  
with any questions. 
6.1.5 
Supporting Documentation to be Submitted to the Alliance 
This study requires supporting documentation for diagnosis, response, progression, other. 
Supporting documentation will include pathology and radiology reports, and these must be 
submitted at the following time points: 
• 
Baseline: Pathology report, radiology report 
• 
Restaging: Radiology report 
• 
Progression: Pathology report (if applicable), radiology report 
Supporting documentation is to be submitted via Rave. 
6.2 
Specimen Collection and Submission  
Correlative Science Manual (CSM): The Alliance A021703 Correlative Science Manual 
(CSM) contains instructions for specimen collection, processing, and shipping. The manual 
can be found on the study-specific webpage on the Alliance and CTSU websites. Questions 
regarding the CSM should be directed to the contact(s) specified in the manual. 
For all patients registered to Alliance A021703: Plasma 25(OH)D level testing will be conducted 
using the whole blood specimens. The submission of these samples for plasma 25(OH)D testing 
is required for all patients registered to this study, including those who are found to be ineligible 
and those who do not receive protocol therapy. 
For patients consented to A021703 Biobanking: All participating institutions must ask patients 
for their consent to participate in the biobanking for future correlative studies, although patient 
participation is optional. Rationale for these studies are described in Section 14.3. For patients 
who consent to participate, tissue, blood, and/or stool will be collected at the following time 
points for these future studies: 
 

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Prior to 
initiation of 
treatment 
Prior to 
treatment 
on C3D1 
Prior to 
treatment 
on C5D1 
Prior to 
treatment 
on C9D1 
At treatment 
discontinuation 
Mandatory for all patients registered to A021703: 
Plasma and Buffy Coats 
from Whole Blood 
1 x 5 mL 
 
1 x 5 mL 
1 x 5 mL 
1 x 5 mL 
For patients consented to A021703 Biobanking, submit the following: 
Archival Tumor Tissue 
X 
 
 
 
 
Plasma from Whole 
Blood 
3 x 10 mL 
 
3 x 10 mL 
3 x 10 mL 
3 x 10 mL 
Serum from Whole 
Blood 
1 x 10 mL 
 
1 x 10 mL 
1 x 10 mL 
 1 x 10 mL 
Stool 
X 
X 
X 
 
X 
 
6.3 
Imaging Report Submission 
Local interpretation imaging reports should be entered into Rave. Reports must be submitted 
from baseline to disease progression. See Section 5.0 for additional details. For patients who go 
off study treatment for reasons other than disease progression (i.e. toxicity) please continue to 
collect images until disease progression. 
De-identify the patient data report using institutional procedures to remove patient name and 
medical record number while preserving the Alliance patient ID number and protocol number. 
6.4 
Diet and Lifestyle Questionnaire Completion and Submission 
The patient-completed questionnaire booklet for this study will be sent to the registering 
institution within two (2) weeks of patient registration/randomization (see Section 4.3 for further 
information). A sample of the questionnaire booklet is available as a separate document on the 
Alliance and CTSU websites for reference and IRB submission only. It is not to be used for 
patient completion. The booklet must be given to patients to complete and patients should be 
instructed to return the booklet to site staff in person; it is recommended that the measure be 
completed during a physician visit and/or chemotherapy session. Patients must complete the 
questionnaire in booklet format. 
Verbal administration of the measure for visually impaired patients is permitted if the measure 
and verbal administration of the measure is conducted in a language understandable to the 
patients. 
The booklet is to be administered within 4 weeks after enrollment.  
The Diet and Lifestyle Questionnaire is available in English. Completion of the Diet and 
Lifestyle Questionnaire booklet is mandatory for all patients registered to this trial who are able 
to speak, read, and/or understand this language. Ad-hoc translation of patient-completed 
measures is not permitted. 
Submission of Completed Booklets: The completed booklets are to be returned to the Diet and 
Lifestyle Coordination Office by site staff via the pre-paid envelope provided to the following 
address: 
 
 
 
 

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7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 14 days of registration.  
For questions regarding treatment, please see the study contacts page.  
It is acceptable for individual chemotherapy doses to be delivered ≤ a 24-hour (business day) window 
before and after the protocol-defined date for Day 1 of a new cycle. For example, if the treatment due 
date is a Friday, the window for treatment includes the preceding Thursday through the following 
Monday. In addition, patients are permitted to have a new cycle of chemotherapy delayed up to 7 
days for major life events (e.g., serious illness in a family member, major holiday, vacation that 
cannot be rescheduled) without this being considered a protocol violation. Documentation to justify 
this delay should be provided. 
This is a randomized, double-blind trial. Blinded, patient-specific clinical supplies of high-dose 
vitamin D3/standard-dose vitamin D3 will be requested by the clinical site via the A021703 Vitamin 
D3 Order Form at the time of randomization and should arrive at the clinical site ≤ approximately 7-
10 days of submitting the request (see Section 10.2). 
Patients will be randomized in a 1:1 fashion to receive either chemotherapy + bevacizumab + high-
dose vitamin D3 (Arm 1, experimental arm) or chemotherapy + bevacizumab + standard-dose vitamin 
D3 (Arm 2, control arm). Chemotherapy will consist or either mFOLFOX6 or FOLFIRI, and the 
regimen administered is per treating physician discretion. The chemotherapy regimen administered 
must remain consistent for the duration of the trial (i.e. patients cannot switch from one chemotherapy 
regimen to the other once protocol treatment has been initiated). The chosen chemotherapy regimen 
must be declared prior to patient randomization as chemotherapy regimen is a stratification 
factor used in this trial; see Section 4.5. Bevacizumab or an FDA-approved biosimilar to 
bevacizumab is allowed; the use of bevacizumab or a biosimilar should remain consistent for the 
duration of the trial for each patient. Treatment will continue until disease progression or 
unacceptable adverse event for a maximum period of 5 years from registration. 
7.1 
Chemotherapy + Bevacizumab + Vitamin D3 
Protocol therapy for all patients will consist of chemotherapy (mFOLFOX6 or FOLFIRI) + 
bevacizumab administered intravenously starting on Day 1 of each 14-day cycle and vitamin 
D3 taken orally on Days 1-14 of each 14-day cycle. Administration schedules for bevacizumab 
with mFOLFOX6 and FOLFIRI can be found in the tables below and are provided as general 
guidelines only; standard institutional procedures should be followed. 
Patients will be randomized in a double-blind fashion to either high-dose vitamin D3 (4,000 
IU/day) or standard-dose vitamin D3 (400 IU/day) with an administration schedule as follows: 
• 
Arm 1 – High-dose Vitamin D3 
o Cycle 1 (Loading Dose Period) 
▪ 
Two (2) 4,000 IU capsules by mouth for a total dose of 8,000 IU/day 
• 
Dispensed as one 14-count bottle of 4,000 IU capsules and one 
100-count bottle of 4,000 IU capsules with instructions to take 
one capsule from each bottle at the same time once daily for 14 
days; see Section 10.2.  
o Cycle 2 and All Subsequent Cycles 

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▪ 
One (1) 4,000 IU capsule by mouth for a total dose of 4,000 IU/day 
• 
Dispensed as 100-count bottle of 4,000 IU capsules with 
instructions to take one capsule once daily; see Section 10.2. 
Note: the initial 100-count bottle of 4,000 IU capsules 
dispensed at Cycle 1 will continue to be used for subsequent 
cycles until a new 100-count bottle is needed. 
• 
Arm 2 – Standard-dose Vitamin D3 
o Cycle 1 (Loading Dose Period) 
▪ 
One (1) 400 IU capsule and one (1) placebo capsule by mouth for a 
total dose of 400 IU/day 
• 
Dispensed as one 14-count bottle of placebo capsules and one 
100-count bottle of 400 IU capsules with instructions to take 
one capsule from each bottle at the same time once daily for 14 
days; see Section 10.2. 
o Cycle 2 and All Subsequent Cycles 
▪ 
One (1) 400 IU capsule by mouth for a total dose of 400 IU/day 
• 
Dispensed as 100-count bottles of 400 IU capsules with 
instructions to take one capsule once daily; see Section 10.2. 
Note: the initial 100-count bottle of 400 IU capsules dispensed 
at Cycle 1 will continue to be used for subsequent cycles until 
a new 100-count bottle is needed. 
Patients will be asked to complete a Medication Diary during treatment with vitamin D3; see 
Appendix II. 
Administration Schedule for mFOLFOX6 + Bevacizumab + Vitamin D3: 
All patients must receive the specific doses listed below in the table for Cycle 1 (i.e. dose level 
0); thereafter, dose modifications are per treating physician discretion and local institutional 
standard; see Section 8.2. Agents should be administered per local institutional standards, 
however, oxaliplatin and continuous-infusion 5-fluorouracil should continue to be administered 
for all cycles until unacceptable toxicity. If toxicity arises that requires dose modification and is 
thought to be related to 5-fluorouracil, treating physicians may wish to first dose-modify or 
discontinue the bolus administration, rather than the continuous-infusion 5-fluorouracil. 
Vitamin D3 can be taken either before or after chemotherapy + bevacizumab. 
Agent 
Dose 
Route 
Duration 
Day 
ReRx 
Bevacizumab* 
5 mg/kg 
IV 
Institutional Standard 
Day 1 
Every 14 Days 
Oxaliplatin 
85 mg/m2 
IV 
Institutional Standard 
Day 1 
Every 14 Days 
Leucovorin 
400 mg/m2 
IV 
Institutional Standard 
Day 1 
Every 14 Days 
5-Fluorouracil 
400 mg/m2 
IV Bolus 
Institutional Standard 
Day 1 
Every 14 Days 
5-Fluorouracil 
2400 mg/m2 
CIV 
Institutional Standard 
Days 
1-3 
Every 14 Days 
* 
Bevacizumab may be omitted on Cycle 1 Day 1 per treating physician’s discretion. 

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Additionally, patients will take two (2) vitamin D3 capsules by mouth for Days 1-14 of Cycle 
1, and then patients will take one (1) vitamin D3 capsule by mouth for Days 1-14 of Cycle 2 and 
all subsequent cycles. 
Administration Schedule for FOLFIRI + Bevacizumab + Vitamin D3: 
All patients must receive the specific doses listed below in the table for Cycle 1 (i.e. dose level 
0); thereafter, dose modifications are per treating physician discretion and local institutional 
standard; see Section 8.2. Agents should be administered per local institutional standards, 
however, irinotecan and continuous-infusion 5-fluorouracil should continue to be administered 
for all cycles until unacceptable toxicity. If toxicity arises that requires dose modification and is 
thought to be related to 5-fluorouracil, treating physicians may wish to first dose-modify or 
discontinue the bolus administration, rather than the continuous-infusion 5-fluorouracil. 
Vitamin D3 can be taken either before or after chemotherapy + bevacizumab. 
Agent 
Dose 
Route 
Duration 
Day 
ReRx 
Bevacizumab* 
5 mg/kg 
IV 
Institutional Standard 
Day 1 
Every 14 Days 
Irinotecan 
180 mg/m2 
IV 
Institutional Standard 
Day 1 
Every 14 Days 
Leucovorin 
400 mg/m2 
IV 
Institutional Standard 
Day 1 
Every 14 Days 
5-Fluorouracil 
400 mg/m2 
IV Bolus 
Institutional Standard 
Day 1 
Every 14 Days 
5-Fluorouracil 
2400 mg/m2 
CIV 
Institutional Standard 
Days 
1-3 
Every 14 Days 
* 
Bevacizumab may be omitted on Cycle 1 Day 1 per treating physician’s discretion. 
Additionally, patients will take two (2) vitamin D3 capsules by mouth for Days 1-14 of Cycle 
1, and then patients will take one (1) vitamin D3 capsule by mouth for Days 1-14 of Cycle 2 and 
all subsequent cycles. 
In order to preserve the double-blind, plasma 25(OH)D levels should not be routinely checked 
while the patient is on study. Plasma 25(OH)D levels will be assayed only as part of the research 
blood samples collected during the study. If there are concerns related to a participant’s vitamin 
D3 status, the Study Chair should be contacted for further discussion. 
7.2 
Imaging 
Imaging scans should be performed at baseline and then after every 4 cycles of treatment, prior 
to Day 1 of the upcoming cycle (i.e., prior to Cycles 5, 9, 13, etc.). CT scans are preferred over 
MRI and should be used if possible (unless the patient has a medical contraindication). CT scans 
should be acquired at approximately 70 seconds after IV contrast administration (to ensure 
maximum enhancement of the liver parenchyma in most patients). The acquired images should 
be reconstructed using axial slice thickness < 5 mm, preferably 2.5 mm, with sagittal and coronal 
reformat. Thinner axial images (2.5 mm) help avoid volume averaging, which may blur 
metastatic margins, and enhance the measurement accuracy. The same imaging modality used 
at baseline must be used throughout the study to enhance consistency.  
Treatment decisions will be based on local investigator/radiologist assessment of response. 

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8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other treatment which would be considered 
treatment for the primary neoplasm or impact the primary endpoint.  
This includes any surgical intervention, radiotherapy, cryotherapy, ablation, etc., 
performed on the primary neoplasm. 
8.1.2 
Patients should receive full supportive care while on this study. 
This includes blood product support, antibiotic treatment, and treatment of other newly 
diagnosed or concurrent medical conditions. All blood products and concomitant 
medications such as antidiarrheals, analgesics, and/or antiemetics received from the first 
day of study treatment administration until 30 days after the final dose will be recorded in 
the medical records. 
8.1.3 
Treatment with hormones or other chemotherapeutic agents may not be 
administered except for: 
Steroids given for adrenal failure; hormones administered for non-disease-related 
conditions (e.g. insulin for diabetes); and intermittent use of dexamethasone as an 
antiemetic. 
8.1.4 
Antiemetics may be used at the discretion of the treating physician. 
Prior to the administration of mFOLFOX6 or FOLFIRI, premedication with antiemetics, 
such as serotonin (5HT3) antagonists (i.e., ondansetron, granisetron) with or without 
dexamethasone may be used at the treating physician’s discretion or according to 
institutional standards. 
8.1.5 
Diarrhea management is per the discretion of the treating physician. 
Diarrhea could be managed conservatively with medications such as loperamide. Treating 
physicians may wish to start loperamide at the earliest sign of 1) a poorly formed or loose 
stool, 2) the occurrence of 1-2 more bowel movements than usual in one day, or 3) an 
increase in stool volume or liquidity. Treating physicians may also wish to provide patients 
with instructions for loperamide use at the initial treatment visit and instructions to 
purchase the medication over-the-counter so that they have sufficient supply on hand in 
case antidiarrheal support is required. Patients may be instructed to increase fluid intake to 
help maintain fluid and electrolyte balance during episodes of diarrhea. Local institutional 
standards should be used as dose modification guidelines for diarrhea. 
Patients with severe diarrhea may need to be assessed for intravenous hydration and 
correction of electrolyte imbalances. 
8.1.6 
Palliative radiation therapy may not be administered.  
Patients who require radiation therapy during protocol treatment will be removed from 
protocol therapy. 
8.1.7 
Alliance Policy Concerning the Use of Growth Factors 
The following guidelines are applicable unless otherwise specified in the protocol. 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology Clinical Practice 
Guideline Update. J Clin Oncol 33: 3199-3212, 2015 and American Society of Clinical 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
Oncology – American Society of Hematology Clinical Practice Guideline Update on the 
Use of Epoetin and Darbepoetin in Adult Patients with Cancer. J Clin Oncol 28:4996-5010, 
2010. 
Epoetin (EPO): Use of epoetin in this protocol is prohibited. 
Filgrastim (G-CSF), tbo-filgrastim, and sargramostim (GM-CSF) are allowed. 
White blood cell growth factors (including filgrastim (G-CSF), pegfilgrastim, and other 
FDA-approved white blood cell growth factor biologics) are allowed per treating physician 
discretion. 
1. White blood cell growth factor treatment for patients on protocols that do not 
specify their use is discouraged. 
2. White blood cell growth factor may not be used: 
a. To avoid dose reductions, delays or to allow for dose escalations specified 
in the protocol. 
b. For the treatment of febrile neutropenia the use of CSFs should not be 
routinely instituted as an adjunct to appropriate antibiotic therapy. 
However, the use of CSFs may be indicated in patients who have 
prognostic factors that are predictive of clinical deterioration such as 
pneumonia, hypotension, multi-organ dysfunction (sepsis syndrome) or 
fungal infection, as per the ASCO guidelines. Investigators should 
therefore use their own discretion in using the CSFs in this setting. The 
use of CSF (filgrastim/pegfilgrastim) must be documented and reported 
(e.g. on CRFs per protocol requirements). 
c. If white blood cell growth factors are used, they must be obtained from 
commercial sources. Selection of white blood cell growth factor products 
should be per institutional guidelines. 
8.1.8 
Hypersensitivity/Infusion Reactions 
Treat hypersensitivity and infusion reactions to protocol therapy as per institutional 
standards. 
8.1.9 
Supplements and Herbal Medications 
Patients should not receive any supplements containing vitamin D, calcium supplements, 
or herbal medications/treatments while on this study. 
8.1.10 Vitamin D Depleting Drugs 
Patients should not receive chronic corticosteroids, lithium, phenobarbital, phenytoin, 
quinidine, isoniazid, and/or rifampin, all of which can cause vitamin D depletion, while on 
this study. Short-term corticosteroids as antiemetic therapy for chemotherapy are 
permitted; see Section 8.1.4. 
8.1.11 Cold-induced Sensory Neuropathy 
Participants should be counseled to avoid cold drinks, chewing of ice chips, and exposure 
to cold water or air because the neurotoxicity often seen with oxaliplatin appears to be 
exacerbated by exposure to cold. The period of time during which the participant is at risk 
for these cold-induced sensory neuropathies is not well documented. Participants should 
exercise caution regarding cold exposure during the treatment period. Peripheral sensory 
neuropathies can occur at any time after receiving oxaliplatin therapy. 

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8.1.12 Surgery/Metastasectomy 
Participants who undergo interventional therapy for metastases (e.g., surgical resection, 
radiofrequency ablation, transarterial embolization) will do so according to standard 
institutional practice. For participants for whom an elective surgery or procedure is 
contemplated, the Study Chair should be notified via email prior to any planned 
intervention. Participants may be allowed to continue on protocol therapy with 
chemotherapy + bevacizumab + vitamin D3 post-intervention if protocol therapy has been 
held for ≤ 28 days, if they continue to have measurable disease per RECIST v1.1 outside 
of the treated metastatic lesion(s) post-intervention, and if the continuation of protocol 
therapy has been discussed with the Study Chair. 
8.2 
Dose Modifications 
If multiple adverse events are seen, administer dose based on greatest reduction required for any 
single adverse event observed. Reductions or increases apply to treatment given in the preceding 
cycle and are based on adverse events observed since the prior dose. 
If more than one of these apply, use the most stringent (i.e. the greatest dose reduction.) 
AERS reporting may be required for some adverse events; see Section 9.0. 
If a new cycle of chemotherapy is delayed, then bevacizumab should also be delayed. 
If vitamin D3 administration is delayed, chemotherapy + bevacizumab administration may 
continue.  
If chemotherapy + bevacizumab are delayed, then vitamin D3 should continue (provided that 
vitamin D3 is not the affecting agent). 
If any agent is delayed due to toxicity for ≥ 4 weeks, counting from the originally scheduled day 
of treatment that was held, discontinue agent. 
If vitamin D3 is permanently discontinued for any reason prior to disease progression, the 
patient will be discontinued from the study. Any further treatment will be “off study” per treating 
physician discretion; see Section 12.0.  
If bevacizumab administration is permanently discontinued for any reason prior to disease 
progression, chemotherapy should be continued on Day 1 of every 14-day cycle and vitamin D3 
should continue orally once daily.  
If chemotherapy administration is permanently discontinued for any reason prior to disease 
progression, patients will not be allowed to switch to the other chemotherapy regimen. 
Bevacizumab administration may continue on Day 1 of every 14-day cycle and vitamin D3 
administration may continue orally once daily.  
If oxaliplatin or irinotecan administration is permanently discontinued for any reason prior to 
disease progression (e.g. grade 3 progressive sensory or motor neuropathy), 5-FU (particularly 
the continuous-infusion 5-fluorouracil) and leucovorin, bevacizumab, and vitamin D3 
administration should continue. Oxaliplatin or irinotecan may be resumed at treating physician’s 
discretion; however switching from one agent to the other is not permitted. 
8.2.1 
Dose Modifications for Vitamin D3 
There will be no dose level reductions for vitamin D3 on this study, only dose delays. 
8.2.1.1 Hypercalcemia 
For grade 2 hypercalcemia, delay vitamin D3 until toxicity improves to grade ≤ 1, then 
resume at the same dose. If the toxicity recurs, then permanently discontinue vitamin D3. 

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For grade ≥ 3 hypercalcemia, permanently discontinue vitamin D3. 
8.2.1.2 Renal and Urinary Toxicities 
For any grade renal calculi (i.e. kidney stones), permanently discontinue vitamin D3.  
8.2.1.3 Other Non-Hematologic Toxicities 
For all other persistent grade 2 toxicities or grade ≥ 3 toxicities that are clinically 
significant and considered at least possibly related to vitamin D3, delay vitamin D3 
until toxicity improves to grade ≤ 1, then resume at the same dose. 
For second recurrences of persistent grade ≥ 2 toxicities that are clinically significant 
and considered at least possibly related to vitamin D3, permanently discontinue vitamin 
D3. 
8.2.2 
Dose Modifications for mFOLFOX6 and FOLFIRI 
Treating physicians should follow local institutional standard practice guidelines for 
further dose modifications related to the mFOLFOX6 and/or FOLFIRI chemotherapy 
regimens. Oxaliplatin, irinotecan, and continuous-infusion 5-fluorouracil should continue 
to be administered for all cycles until unacceptable toxicity. However, if toxicity arises that 
requires dose modification and is thought to be related to 5-fluorouracil, treating physicians 
may wish to first dose-modify or discontinue the bolus administration, rather than the 
continuous-infusion 5-fluorouracil. 
8.2.3 
Dose Modifications for Bevacizumab 
Treating physicians should follow local institutional standard practice guidelines for 
further dose modifications related to bevacizumab. 
8.2.4 
Dose Modifications for Obese Patients 
There is no clearly documented adverse impact of treatment of obese patients when dosing 
is performed according to actual body weight. Therefore, all dosing is to be determined 
solely by actual weight without any modification unless explicitly described in the 
protocol. This will eliminate the risk of calculation error and the possible introduction of 
variability in dose administration. Failure to use actual body weight in the calculation of 
drug dosages will be considered a major protocol deviation. Physicians who are 
uncomfortable with calculating doses based on actual body weight should recognize that 
doing otherwise would be a protocol violation. Physicians may consult the published 
guidelines of the American Society of Clinical Oncology Appropriate Chemotherapy 
Dosing for Obese Adult Patients with Cancer: American Society of Clinical Oncology 
Clinical Practice Guideline. J Clin Oncol 30(13): 1553-1561, 2012. 
8.3 
Unblinding Procedures  
Unblinding can be done only in cases of an emergency. Follow the directions below to unblind 
patient treatment. Please note that if a treatment assignment is unblinded, the patient must 
discontinue protocol therapy. 
8.3.1 
Emergency Unblinding Procedures 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at 
least possibly related to the investigational agent and for which unblinding would influence 
treatment decisions; or 2) medication error, such as accidental overdose. Expected adverse 
events are listed in the “Toxicities” section below. 

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Contact the Alliance Executive Officer on call by calling 
 pressing 1 to 
speak with an operator, and then asking for pager 
to return the call. 
The institution must provide the following information to the Alliance Executive Officer: 
• 
Alliance study ID (i.e. “A021703”) 
• 
Alliance patient ID number (e.g. “999999”) 
• 
Patient initials (e.g. “L,FM”) 
• 
Institution name 
• 
Name and telephone number of treating physician 
• 
Name and contact information of person requesting the unblinding procedure 
• 
Name and contact information of person to inform of treatment assignment 
• 
Reason for emergency unblinding  
Please remember that emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation. After the Executive Officer deems unblinding is 
warranted, the treatment assignment will be provided to the contact person at the treating 
site. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
 
Attribution 
to 
protocol treatment for each adverse event must be determined by the investigator and reported on the 
required forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further 
details on AE reporting procedures.  
9.1 
Routine Adverse Event Reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the Study Calendar in Section 5.0. For this trial, the Form, “Adverse Events” 
is used for routine AE reporting in Rave. 
9.1.1 
Solicited Adverse Events 
The following adverse events are considered "expected" and their presence/absence should 
be solicited, and severity graded, at baseline and for each cycle of treatment by CTCAE. 
CTCAE v5.0 Term 
CTCAE v5.0 System Organ Class (SOC) 
Neutrophil count decreased 
Investigations 
Platelet count decreased 
Investigations 
Diarrhea 
Gastrointestinal disorders 

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Nausea 
Gastrointestinal disorders 
Vomiting 
Gastrointestinal disorders 
Peripheral sensory neuropathy 
Nervous system disorders 
Hypertension 
Vascular disorders 
 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the 
Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on 
Case Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
 
a) 
Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 
days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) 
Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. The descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0 will be utilized for AE reporting. The CTCAE 
is 
identified 
and 
located 
on 
the 
CTEP 
website 
at: 
 All appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS).  
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note: All deaths on study require both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause should be provided. 
 
 

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9.3.1 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE ≤ 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
 

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9.3.2 
Expedited AE Reporting Timelines Defined 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS ≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 
calendar days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs following 
treatment with an agent under an IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting 
Requirements 
All adverse events reported via CTEP-AERS (i.e. serious adverse events) should also be 
forwarded to your local IRB. 
Grade ≤ 4 anemia, neutropenia, or thrombocytopenia resulting in hospitalization does not 
require CTEP-AERS, but should be submitted as part of study results. All other grade 3, 4, 
or 5 adverse events that precipitate hospitalization or prolong an existing hospitalization 
must be reported via CTEP-AERS. 
New primary malignancies should be reported using Medidata Rave®. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.” 
Evidence that the death was a manifestation of underlying disease (e.g. radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the 
investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, 
probably, or definitely related to the investigational agent/intervention. 
Pregnancy Loss: 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” 
• 
Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” 
under the Pregnancy, puerperium and perinatal conditions SOC. 
• 
A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes 
this event as a patient death. 

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A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 
All new malignancies must be reported via CTEP-AERS whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e. solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. 
Secondary Malignancy: 
• 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g. 
treatment 
with 
investigational 
agent/intervention, 
radiation, 
or 
chemotherapy). A secondary malignancy is not considered a metastasis of the 
initial neoplasm. 
• 
CTEP requires all secondary malignancies that occur following treatment with an 
agent under an IND be reported via CTEP-AERS. Three options are available to 
describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g. acute myelocytic 
leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
Second Malignancy: 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting unless otherwise specified.  
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, 
any associated risk factors or evidence regarding how long the new malignancy may have 
been present, when and how the new malignancy was detected, molecular characterization 
or cytogenetics of the original tumor (if available) and of any new tumor, and new 
malignancy treatment and outcome, if available. 
Treatment expected adverse events include those listed in Section 10.0 and in the package 
insert. 
CTEP-AERS reports should be submitted electronically. 
10.0 DRUG INFORMATION 
10.1 
General Considerations 
The total administered dose of chemotherapy may be rounded up or down within a range of 10% 
of the actual calculated dose.  
It is not necessary to change the doses of standard chemotherapy drugs due to changes in weight 
unless the calculated dose changes by ≥10% or per institutional standard procedures. 
All study agents are to be administered at the registering institution.  

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If the Group credited for enrollment is a non-Alliance Group, then other requirements from the 
credited Group may apply. 
10.2 
Vitamin D3 (NSC# 375571) 
Investigators ordering and/or dispensing supplied agents at any time for study treatment must 
be currently registered with PMB, DCTD, NCI and have an active registration status. A 
registered investigator must co-sign for other personnel prescribing the supplied agents. 
Procurement 
Vitamin D3 is patient specific, and may NOT be dispensed to another patient.  
Patient-specific supply may be confirmed by checking the patient ID number included on the 
drug invoice and drug bottles.  
Vitamin D3 will be provided by Pharmavite, LLC and distributed by McKesson Clinical 
Research Services. Sites will procure initial and subsequent supplies of vitamin D3 by 
submitting the Vitamin D3 Order Form on the A021703 study page on the Alliance and CTSU 
websites. Submission instructions are outlined on the form. 
Study drug cannot be shipped post-distribution. 
McKesson Clinical Research Services will ship patient-specific, blinded drug supplies. The drug 
bottles will be labeled with the patient ID number. Additional details regarding drug supply can 
be found on the Vitamin D3 Order Form. 
Formulation 
Vitamin D3 and placebo will be provided as liquid gel capsules containing the following 
ingredients: 
Ingredients 
Function 
Vitamin D3 
400 IU (%) 
Vitamin D3 
4000 IU (%) 
Placebo (%) 
Soybean Oil, USP 
Carrier 
59.3375 
57.6951 
59.52 
Gelatin, NF 
Shell 
27.2300 
27.2300 
27.23 
Glycerin, USP 99.5% 
Shell Plasticizer 
10.0100 
10.0100 
10.01 
Purified Water, USP 
Pharmaceutical 
Solvent 
3.2400 
3.2400 
3.20 
Corn Oil 
Carrier 
0.1770 
1.7702 
- 
Cholecalciferol 
Dietary Active 
0.0046 
0.0456 
- 
Cod Liver Oil 
Dietary Active 
0.0009 
0.0091 
- 
Storage and Stability 
Vitamin D3 capsules must be stored in its unopened original packaging at room temperature 
(15-30⁰C) and protected from excessive heat. 
Investigator’s Brochure Availability 
The Investigator’s Brochure (IB) for vitamin D3 may be obtained by contacting the Alliance 
Central Protocol Operations Program Office at 
Note: a Chemistry, 
Manufacturing, and Controls (CMC) document is being used in lieu of an IB for vitamin D3. 
Preparation 
Vitamin D3 will be provided in tamper-proof bottles as blinded, matched drug supplies. Local 
pharmacies may adhere labels directly to the bottles. 

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Administration 
Vitamin D3 will be taken orally by mouth as described in Section 7.1. 
When agents are required to be dispensed in the original manufacturer’s drug product container 
and a site’s policy dictates provision of exact quantities for dispensing purposes, removal of the 
extra agent from the manufacturer’s container is the only way this can be satisfied and destroying 
the extra is allowed. 
Drug Accountability 
NCI Investigational Agent Accountability Record for Oral agents (manual or electronic form) 
should be used to document receipt, dispensing, patient’s returns, and disposal of supplied 
vitamin D3. 
Ninety days after the patient is off treatment, any expired or remaining supplies should be 
destroyed according to institutional procedure. 
Drug Interactions 
Aluminum hydroxide: Vitamin D may increase the serum concentration of aluminum hydroxide, 
leading to increased serum aluminum concentration. 
Mineral oil: mineral oil may interfere with the absorption of vitamin D analogs, leading to 
decreased serum concentration of vitamin D. 
Calcium salts may increase the adverse/toxic effect of vitamin D. 
Thiazide and thiazide-like diuretics may enhance the hypercalcemic effect of vitamin D. 
Pharmacokinetics 
Vitamin D is absorbed in the small intestine and excreted to feces. It is inactive until 
hydroxylated hepatically to 25-hydroxyvitamin D (calcifediol, 25(OH)D), then to the active 
metabolite 1, 25-dihydroxyvitamin D (calcitriol) in the kidney.  
The half-life of hydroxylated calcifediol is 2 to 3 weeks and calcitriol is about 4 hours. 
Adverse Events 
Vitamin D toxicity may occur with excessive doses; symptoms may include nausea, vomiting, 
loss of appetite, constipation, dehydration, fatigue, irritability, confusion, weakness and/or 
weight loss. Effects of vitamin D can last ≥ 2 months after therapy is discontinued. 
10.3 
Fluorouracil (Adrucil®, 5FU, NSC# 19893) 
Procurement 
Commercial supplies. Institutional pharmacy shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection 50 mg/mL (10 mL, 20 mL, 50 mL, and 100 mL). 
Storage and Stability 
Store intact vials at room temperature and protect from light. A slight discoloration may occur 
with storage but usually does not denote decomposition. If exposed to cold, a precipitate may 
form; gentle heating to 60ºC will dissolve the precipitate without impairing the potency. 
Solutions in 50 – 1000 mL 0.9% NaCl or D5W or undiluted solutions in syringes are stable for 
72 hours at room temperature. Fluorouracil should not be co-administered with either diazepam, 

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doxorubicin, daunorubicin, idarubicin, cisplatin, or cytarabine. However, fluorouracil and 
leucovorin are compatible for 14 days at room temperature. Fluorouracil is compatible with 
vincristine, methotrexate, and cyclophosphamide 
Preparation 
Dilute in 50 – 1000 mL of 0.9% NaCl or D5W. 
Administration 
Fluorouracil may be given IV bolus or IV infusion. Refer to the treatment section for specific 
administration instructions. Avoid extravasation, may be an irritant. 
Drug Interactions 
Fluorouracil may increase effects of warfarin. Avoid ethanol (due to GI irritation). Avoid black 
cohosh. 
Pharmacokinetics 
Distribution: Vd ~ 22% of total body water; penetrates extracellular fluid, CSF, and third space 
fluids (e.g. pleural effusions and ascitic fluid) 
Metabolism: Hepatic (90%); via a dehydrogenase enzyme; Fluorouracil must be metabolized to 
be active. 
Half-life Elimination: Biphasic: Initial: 6-20 minutes; two metabolites, FdUMP and FUTP, have 
prolonged half-lives depending on the type of tissue. 
Excretion: Lung (large amounts as CO2); urine (5% as unchanged drug) in 6 hours. 
Adverse Events 
Consult the package insert for the most current and complete information. 
Common Known Potential Toxicities, > 10%: 
Dermatologic: Dermatitis, pruritic maculopapular rash, alopecia. 
Gastrointestinal (route and schedule dependent): Heartburn, nausea, vomiting, anorexia, 
stomatitis, esophagitis, anorexia, diarrhea. GI toxicity (anorexia, nausea, and vomiting) is 
generally more severe with continuous-infusion schedules. 
Emetic Potential: <1000 mg: Moderately low (10% to 30%) ≥ 1000 mg: Moderate (30% to 60%) 
Hematologic: Leukopenia; Myelosuppressive (tends to be more pronounced in patients 
receiving bolus dosing of FU). Decreased white blood cell count with increased risk of infection; 
decreased platelet count with increased risk of bleeding. 
Local: Irritant chemotherapy. 
Less Common Known Potential Toxicities, 1% - 10%: 
Dermatologic: Dry skin 
Gastrointestinal: GI ulceration 
Rare Known Potential Toxicities, <1% (Limited to Important or Life-threatening): 
Cardiac enzyme abnormalities, chest pain, coagulopathy, dyspnea, ECG changes similar to 
ischemic changes, hepatotoxicity; hyperpigmentation of nail beds, face, hands, and veins used 
in infusion; hypotension, palmar-plantar syndrome (hand-foot syndrome), photosensitization. 

Alliance A021703 
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Update #02
 
 
 
Cerebellar ataxia, headache, somnolence, ataxia are seen primarily in intracarotid arterial 
infusions for head and neck tumors. 
Nursing Guidelines 
Monitor complete blood count and platelet count. Instruct patient to report signs and symptoms 
of infection, unusual bruising or bleeding to the physician. 
Administer antiemetics as indicated. 
Diarrhea may be dose–limiting; encourage fluids and treat symptomatically. 
Assess for stomatitis; oral care measures as indicated. May try vitamin E oil dabbed on sore, six 
times daily. Cryotherapy recommended with IV push administration. 
Monitor for neurologic symptoms (headache, ataxia). 
Inform patient of potential alopecia. 
Those patients on continuous infusion may need instruction regarding central intravenous 
catheters and portable intravenous or IA infusion devices. 
5FU–induced conjunctivitis is a common problem. Advise patient to report any eye soreness or 
redness to the healthcare team. 
Photosensitivity may occur. Instruct patients to wear sun block when outdoors. 
10.4 
Leucovorin Calcium (NSC# 3590) 
Procurement 
Commercial supplies. Institutional pharmacy shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
NOTE: Levoleucovorin is not the same as leucovorin calcium. 
Leucovorin calcium is available as: 
• 
Solution for Injection 100 mg/10 mL (10 mL, 30 mL) 
• 
Lyophilized Powder for Injection 50 mg, 100 mg, 200 mg, 350 mg, 500 mg 
Storage and Stability 
Powder for Injection: Store at room temperature of 25°C (77°F). Protect from light. Solutions 
reconstituted with bacteriostatic water for injection U.S.P., must be used within 7 days. 
Solutions reconstituted with SWFI must be used immediately. Parenteral admixture is stable for 
24 hours stored at room temperature (25°C) and for 4 days when stored under refrigeration 
(4°C). 
Solution for Injection: Prior to dilution, store vials under refrigeration at 2°C to 8°C (36°F to 
46°F). Protect from light. 
Preparation 
Powder for Injection: Reconstitute with SWFI or BWFI; dilute with D5W or NS for infusion. 
When doses > 10 mg/m2 are required, reconstitute using sterile water for injection, not a solution 
containing benzyl alcohol. 
Solution for Injection: Dilute in D5W or NS for infusion. 
 
 

Alliance A021703 
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Update #02
 
 
 
Administration 
Should be administered IV infusion (2 hours) and is not intended for intrathecal use. 
Combination Therapy with Fluorouracil: Fluorouracil is usually given after, or at the midpoint, 
of the leucovorin infusion. Leucovorin is usually administered by IV infusion. Other 
administration schedules have been used; refer to individual protocols. 
Drug Interactions 
Capecitabine: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of 
Capecitabine. Risk C: Monitor therapy. 
Fluorouracil (Systemic): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic 
effect of Fluorouracil (Systemic). This effect is associated with the ability of leucovorin or 
levoleucovorin to enhance the anticancer effects of fluorouracil. Risk C: Monitor therapy. 
Fluorouracil (Topical): Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic 
effect of Fluorouracil (Topical). Risk C: Monitor therapy. 
Fosphenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Fosphenytoin. Risk C: Monitor therapy. 
Glucarpidase: May decrease serum concentrations of the active metabolite(s) of Leucovorin 
Calcium-Levoleucovorin. Specifically, 6S-5-methyltetrahydrofolateconcentrations may be 
reduced. Glucarpidase may decrease the serum concentration of Leucovorin Calcium-
Levoleucovorin. Management: Avoid leucovorin administration within 2 hours of glucarpidase 
dosing. Continue to administer the pre-glucarpidase leucovorin dose for at least the first 48 hours 
after glucarpidase administration, and dose based on methotrexate concentration thereafter. Risk 
D: Consider therapy modification. 
PHENobarbital: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
PHENobarbital. Risk C: Monitor therapy. 
Phenytoin: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Phenytoin. Risk C: Monitor therapy. 
Primidone: Leucovorin Calcium-Levoleucovorin may decrease the serum concentration of 
Primidone. Additionally, leucovorin/levoleucovorin may decrease concentrations of active 
metabolites of primidone (e.g. phenobarbital). Risk C: Monitor therapy. 
Raltitrexed: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of 
Raltitrexed. Risk X: Avoid combination. 
Tegafur: Leucovorin Calcium-Levoleucovorin may enhance the adverse/toxic effect of Tegafur. 
This effect is associated with the ability of leucovorin or levoleucovorin to enhance the 
anticancer effects of fluorouracil. Risk C: Monitor therapy. 
Trimethoprim: Leucovorin Calcium-Levoleucovorin may diminish the therapeutic effect of 
Trimethoprim. Management: Avoid concurrent use of leucovorin or levoleucovorin with 
trimethoprim (plus sulfamethoxazole) for Pneumocystis jiroveci pneumonia. If trimethoprim is 
used for another indication, monitor closely for reduced efficacy. Risk X: Avoid combination. 
Pharmacokinetics 
Absorption: Oral, IM: Well absorbed 
Metabolism: Intestinal mucosa and hepatically to 5-methyl-tetrahydrofolate (5MTHF; active) 
Bioavailability: Saturable at oral doses >25 mg; 25 mg (97%), 50 mg (75%), 100 mg (37%) 

Alliance A021703 
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Update #02
 
 
 
Half-life Elimination: ~4-8 hours 
Time to Peak: Oral: ~2 hours; IV: Total folates: 10 minutes; 5MTHF: ~1 hour 
Excretion: Urine (primarily); feces 
Adverse Events 
Consult the package insert for the most current and complete information. 
Dermatologic: Rash, pruritus, erythema, urticaria 
Hematologic: Thrombocytosis 
Respiratory: Wheezing 
Miscellaneous: Allergic reactions, anaphylactoid reactions 
Nursing Guidelines 
Headache may occur. Advise patient that analgesics such as Tylenol may help. Instruct patient 
to report any headache that is unrelieved. 
Observe for sensitization reaction (rash, hives, pruritus, facial flushing, and wheezing). 
May potentiate the toxic effects of fluoropyrimidine (5FU) therapy, resulting in increased 
hematologic and gastrointestinal (diarrhea, stomatitis) adverse effects. Monitor closely. 
May cause mild nausea or upset stomach. Administer antiemetics if necessary and evaluate for 
their effectiveness. 
10.5 
Oxaliplatin (Eloxatin®, OXAL, NSC# 266046) 
Procurement 
Commercial supplies. Institutional pharmacy shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially Available for Injection as Solution [preservative free]: 5 mg/mL (10 mL, 20 mL, 
and 40 mL). 
Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store intact vials 
in original outer carton at room temperature and do not freeze. According to the manufacturer, 
solutions diluted for infusion are stable up to 6 hours at room temperature or up to 24 hours 
under refrigeration. Oxaliplatin solution diluted with D5W to a final concentration of 0.7 mg/mL 
(polyolefin container) has been shown to retain >90% of its original concentration for up to 30 
days when stored at room temperature or refrigerated; artificial light did not affect the 
concentration (Andre, 2007). As this study did not examine sterility, refrigeration would be 
preferred to limit microbial growth. Infusion solutions do not require protection from light. 
Preparation 
Do not prepare using a chloride-containing solution (e.g. NaCl). Dilution with D5W (250 or 500 
mL) is required prior to administration. 
Administration 
Refer to the treatment section for specific administration instructions. Administer as IV infusion 
over 2 hours. Flush infusion line with D5W prior to administration of any concomitant 

Alliance A021703 
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Update #02
 
 
 
medication. Patients should receive an antiemetic premedication regimen. Cold temperature 
may exacerbate acute neuropathy. Avoid mucositis prophylaxis with ice chips during oxaliplatin 
infusion. 
Drug Interactions 
Increased Effect/Toxicity: Nephrotoxic agents may increase Oxaliplatin toxicity. 
When administered as sequential infusions, observational studies indicate a potential for 
increased toxicity when platinum derivatives (carboplatin, cisplatin, oxaliplatin) are 
administered before taxane derivatives (docetaxel, paclitaxel). 
Decreased Effect: Oxaliplatin may decrease plasma levels of digoxin 
Pharmacokinetics 
Distribution: Vd: 440 L 
Protein Binding: >90% primarily albumin and gamma globulin (irreversible binding to 
platinum) 
Metabolism: Nonenzymatic (rapid and extensive), forms active and inactive derivative phase: 
16.8 hours 
Excretion: Primarily urine (~54%); feces (~2%) 
Adverse Events 
Consult the package insert for the most current and complete information. Percentages reported 
with monotherapy. 
Common Known Potential Toxicities, > 10%: 
Central nervous system: Fatigue, fever, pain, headache, insomnia 
Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain, constipation, anorexia, stomatitis 
Hematologic: Anemia, thrombocytopenia, leukopenia 
Hepatic: Liver enzymes increased 
Neuromuscular & skeletal: Back pain, peripheral neuropathy (may be dose limiting). The most 
commonly observed oxaliplatin-related toxicity is acute and cumulative neurotoxicity, observed 
in patients treated at doses above 100 mg/m2/cycle. This neurotoxicity has included paresthesias 
and dysesthesias of the hands, feet, and perioral region as well as unusual laryngopharyngeal 
dysesthesias characterized by a loss of sensation of breathing without any objective evidence of 
respiratory distress (hypoxia, laryngospasm, or bronchospasm). OXAL neurotoxicity appears to 
be exacerbated by exposure to cold. Patients on this study will be counseled to avoid cold drinks 
and exposure to cold water or air. Should a patient develop laryngopharyngeal dysesthesia, their 
oxygen saturation should be evaluated via a pulse oximeter; if normal, an anxiolytic agent 
should be given and the patient observed in the clinic until the episode has resolved. Because 
this syndrome may be associated with the rapidity of OXAL infusion, subsequent doses of 
OXAL should be administered as a 6-hour infusion (instead of the normal 2-hour infusion). 
Acute and cumulative neurotoxicities are dose limiting for OXAL. The acute neurotoxicity is 
characterized by paresthesias and dysesthesias that may be triggered or exacerbated by exposure 
to cold. These symptoms occur within hours of exposure and are usually reversible over the 
following hours or days. Cumulative doses of OXAL above 680 mg/m2 may produce functional 
impairment characterized by difficulty performing activities requiring fine sensory-motor 
coordination; impairment is caused by sensory rather than motor changes. 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
The likelihood of experiencing neurotoxicity is directly related to the total cumulative dose of 
OXAL administered. The relative risk of developing neurotoxicity was 10%, 50%, and 75% in 
patients who received total cumulative OXAL doses of 780 mg/m2, 1,170 mg/m2, and 1,560 
mg/m2, respectively. Both acute and cumulative neurotoxicities due to OXAL have lessened in 
82% of patients within 4 to 6 months, and have completely disappeared by 6 to 8 months in 41% 
of patients. In addition, the likelihood that neurologic symptoms will regress has been shown to 
correlate inversely with cumulative dose. 
Respiratory: Dyspnea, cough 
Less Common Known Potential Toxicities, 1% - 10%: 
Cardiovascular: Edema, chest pain, peripheral edema, flushing, thromboembolism 
Central nervous system: Dizziness 
Dermatologic: Rash, alopecia, hand-foot syndrome 
Endocrine & metabolic: Dehydration, hypokalemia 
Gastrointestinal: Dyspepsia, taste perversion, flatulence, mucositis, gastroesophageal reflux, 
dysphagia 
Genitourinary: Dysuria 
Hematologic: Neutropenia 
Local: Injection site reaction 
Neuromuscular & skeletal: Rigors, arthralgia 
Ocular: Abnormal lacrimation 
Renal: Serum creatinine increased 
Respiratory: URI, rhinitis, epistaxis, pharyngitis, pharyngolaryngeal dysesthesia 
Miscellaneous: Allergic reactions, hypersensitivity (includes urticaria, pruritus, facial flushing, 
shortness of breath, bronchospasm, diaphoresis, hypotension, syncope, hiccup 
Rare Known Potential Toxicities, <1% (Limited to Important or Life-threatening): 
Gastrointestinal: Life threatening enteric sepsis secondary to neutropenia and diarrhea. 
Hepatic: Veno-occlusive disease of the liver is a rare serious adverse event that has occurred in 
association with administration of oxaliplatin and fluorouracil. 
Otic: Clinical ototoxicity occurs in less than 1% of patients following oxaliplatin administration, 
and severe ototoxicity has not been reported. 
Nursing Guidelines 
GI toxicity similar to cisplatin occurs with doses above 30 mg/m2. It can be almost constant and 
frequently severe, but not always dose-limiting. Monitor for nausea and vomiting and treat 
accordingly. 
Dose-limiting side effect can be paresthesias of hands, fingers, toes, pharynx, and occasionally 
cramps which develops with a dose-related frequency (>90 mg/m2). Duration of symptoms tend 
to be brief (less than a week) with the first course, but longer with subsequent courses. Phase I 
patients have reported exacerbation of paresthesias by touching cold surfaces or exposure to 
cold. Advise patient of these possibilities and instruct patient to report these symptoms to the 

Alliance A021703 
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Update #02
 
 
 
health care team. Also advise patient to refrain from operating dangerous machinery that 
requires fine sensory-motor coordination, if symptoms appear. 
These sensory neuropathies developed after subsequent courses with increasing intensity (Grade 
3 toxicity after the fourth course) and with increasing duration. In 63% of the patients tested in 
phase I at high doses (135-200 mg/m2), neuropathies became long-term with slow reversal over 
several months. Disabling walking and handwriting difficulties, as well as mouth and throat 
dysesthesias and laryngospasms were seen. Instruct patient to report any swallowing difficulties 
or gait changes. 
OXAL is incompatible with NS. Flush lines with D5W prior to and following OXAL infusion. 
Low back pain is a common side effect, perhaps a form of hypersensitivity reaction. Instruct 
patient in good body mechanics, advise light massage, heat, etc. 
Laryngopharyngeal dysesthesia (LPD) occurs in about 15% of patients and is acute, sporadic, 
and self-limited. It usually occurs within hours of infusion, is induced or exacerbated by 
exposure to cold, and presents with dyspnea and dysphagia. The incidence and severity appear 
to be reduced by prolonging infusion time. Instruct patient to avoid ice and cold drinks the day 
of infusion. 
Comparison of the Symptoms and Treatment of Laryngopharyngeal Dysesthesias and Platinum 
Hypersensitivity Reactions 
 
Treatment anxiolytics, observation in a controlled clinical setting until symptoms abate or at the 
physicians’ discretion oxygen, steroids, epinephrine, bronchodilators; fluids and vasopressors, 
if appropriate 
Alopecia is rare with OXAL alone, but is seen with 5-FU-OXAL combination. Advise patient. 
Mild-moderate diarrhea has been seen – usually of short duration. Treat accordingly. See 
Section 8.1 for ancillary treatment. 
Comparison of the Symptoms and Treatment of Laryngopharyngeal Dysesthesias 
and Platinum Hypersensitivity Reactions 
Clinical Symptoms 
Laryngopharyngeal 
Dysesthesias 
Platinum Hypersensitivity 
Dyspnea 
present 
present 
Bronchospasm 
absent 
present 
Laryngospasm 
absent 
present 
Anxiety 
present 
present 
O2 saturation 
normal 
decreased 
Difficulty swallowing 
present (loss of sensation) 
absent 
Pruritus 
absent 
present 
Urticaria/rash 
absent 
present 
Cold-induced symptoms 
yes 
no 
BP 
normal or increased 
normal or decreased 
Treatment 
anxiolytics, observation in a 
controlled clinical setting 
until symptoms abate or at 
the physicians’ discretion 
oxygen, steroids, epinephrine, 
bronchodilators; fluids and 
vasopressors, if appropriate 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
Respiratory problems (i.e. pulmonary fibrosis, cough, dyspnea, rales, pulmonary infiltrates, 
hypoxia, air hunger and tachypnea) have been observed in patients administered OXAL. In rare 
cases, death has occurred due to pulmonary fibrosis. Please monitor and instruct the patient to 
report any respiratory difficulties and hold OXAL until interstitial lung disease is ruled out for 
cases of Grade ≥ 3. If patient is experiencing shortness of breath, a chest x-ray and assessment 
of oxygenation via either finger oximetry or arterial blood gas evaluation are required to confirm 
the absence or presence of pulmonary infiltrates and/or hypoxia (treat accordingly: no 
intervention, steroids, diuretics, oxygen, or assisted ventilation). 
Veno-occlusive disease (VOD) is a rare but serious complication that has been reported in 
patients receiving oxaliplatin in combination with 5-FU. This condition can lead to 
hepatomegaly, splenomegaly, portal hypertension and/or esophageal varices. Instruct patients 
to report any jaundice, ascites, or hematemesis to the MD immediately as these could be a sign 
of VOD or other serious condition. 
Acute vein irritation can occur with infusion. Apply heat to arm of infusion if you are using a 
peripheral line. However, extravasation of drug can cause severe pain, redness, soreness, and 
exfoliation of the skin in the affected area with loss of affected vein for a long period. If a patient 
has a problem with pain or sclerosis when chemotherapy is given by a peripheral line, then 
placement of a central line should be considered. 
Hemolytic Uremic Syndrome (HUS) may result in kidney damage. Oxaliplatin is to be 
discontinued in cases where hematocrit is <25%, thrombocytopenia <100,000, and creatinine 
1.6 mg/dL. 
Patients may experience sleep disturbances, specifically insomnia. Encourage good sleep 
hygiene, and instruct patient to report any problems with sleep to the MD, to assess for the 
potential use of sleeping aids. 
Cold-induced transient visual abnormalities can be experienced by patients while receiving 
OXAL, although the relationship to OXAL has not been completely determined. Instruct patient 
to report any problems with vision to the MD. 
Extrapyramidal side effects and/or involuntary limb movement has been seen with OXAL 
administration. Patients may also experience restlessness. Instruct patient to report any of these 
side effects to the MD. 
A bolus infusion of OXAL/CAPCIT may increase the risk of developing life-threatening enteric 
sepsis secondary to neutropenia and diarrhea. Patients with grade 4 ANC and grade 3 diarrhea 
should be closely monitored and condition reported to MD for possible hospitalization for 
appropriate hydration and treatment with antibiotics, appropriate for gram negative or anaerobic 
sepsis. Patients should be monitored closely and provided with aggressive supportive care until 
neutropenia and diarrhea resolve. 
10.6 
Irinotecan (Camptosar, NSC# 616348) 
Procurement 
Commercial supplies. Institutional pharmacy shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Commercially available for injection 20 mg/mL (2 mL, 5 mL) [contains sorbitol 45 mg/mL; do 
not use in patients with hereditary fructose intolerance]. 
 
 

Alliance A021703 
Version Date: 09/20/2022 
 
Update #02
 
 
 
Storage and Stability 
Refer to package insert for complete preparation and dispensing instructions. Store intact vials 
at room temperature and protect from light. Due to the relatively acidic pH, irinotecan appears 
to be more stable in D5W than 0.9% NaCl. Solutions diluted in D5W are stable for 24 hours at 
room temperature or 48 hours under refrigeration at 2ºC to 8ºC. Solutions diluted in 0.9% NaCl 
may precipitate if refrigerated. Do not freeze. 
Preparation 
Doses should be diluted in 250-500 mL D5W or 0.9% NaCl to a final concentration of 0.12-2.8 
mg/mL. 
Administration 
Administer by IV infusion, usually over 90 minutes. 
Drug Interactions 
Cytochrome P450 Effect: Substrate (major) of CYP2B6, 3A4 
Increased Effect/Toxicity: CYP2B6 and CYP3A4 inhibitors may increase the levels/effects of 
irinotecan. Bevacizumab may increase the adverse effects of irinotecan (e.g. diarrhea, 
neutropenia). Ketoconazole increases the levels/effects of irinotecan and active metabolite; 
discontinue ketoconazole 1 week prior to irinotecan therapy; concurrent use is contraindicated. 
Decreased Effect: CYP2B6 and CYP3A4 inducers may decrease the levels/effects of irinotecan. 
Ethanol/Nutrition/Herb Interactions Herb/Nutraceutical: St. John’s Wort decreases therapeutic 
effect of irinotecan; discontinue ≥ weeks prior to irinotecan therapy; concurrent use is 
contraindicated. 
Pharmacokinetics 
Distribution: Vd: 33-150 L/m2 
Protein binding, plasma: Predominantly albumin; Parent drug: 30% to 68%, SN-38 (active 
metabolite): ~95% 
Metabolism: Primarily hepatic to SN-38 (active metabolite) by carboxylesterase enzymes; SN-
38 undergoes conjugation by UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a 
glucuronide metabolite. Conversion of irinotecan to SN-38 is decreased and glucuronidation of 
SN-38 is increased in patients who smoke cigarettes, resulting in lower levels of the metabolite 
and overall decreased systemic exposure. SN-38 is increased by UGT1A1*28 polymorphism 
(10% of North Americans are homozygous for UGT1A1*28 allele). Patients homozygous for 
the UGT1A1*28 allele are at increased risk of neutropenia; initial one-level dose reduction 
should be considered for both single-agent and combination regimens. The lactones of both 
Irinotecan and SN-38 undergo hydrolysis to inactive hydroxyl acid forms. 
Half-life elimination: SN-38: Mean terminal: 10-20 hours 
Time to peak: SN-38: Following 90-minute infusion: ~1 hour 
Excretion: Within 24 hours: urine: Irinotecan (11% to 20%), metabolites (SN-38 < 1%, SN-38 
glucuronide, 3%) 
Adverse Events 
Consult the package insert for the most current and complete information including U.S. Boxed 
Warnings pertaining to severe diarrhea and severe myelosuppression. 

Alliance A021703 
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Update #02
 
 
 
Common known potential toxicities, > 10%: 
Cardiovascular: Vasodilation 
Central nervous system: Cholinergic toxicity (includes rhinitis, increased salivation, miosis, 
lacrimation, diaphoresis, flushing and intestinal hyperperistalsis); fever, pain, dizziness, 
insomnia, headache, chills 
Dermatologic: Alopecia, rash 
Endocrine & metabolic: Dehydration 
Gastrointestinal: Late onset diarrhea, early onset diarrhea, nausea, abdominal pain, vomiting, 
cramps, anorexia, constipation, mucositis, weight loss, flatulence, stomatitis 
Hematologic: Anemia, leukopenia, thrombocytopenia, neutropenia 
Hepatic: Bilirubin increased, alkaline phosphatase increased 
Neuromuscular & skeletal: Weakness, back pain 
Respiratory: Dyspnea, cough, rhinitis 
Miscellaneous: Diaphoresis, infection 
Less common known potential toxicities, 1% - 10%: 
Cardiovascular: Edema, hypotension, thromboembolic events 
Central nervous system: Somnolence, confusion 
Gastrointestinal: Abdominal fullness, dyspepsia 
Hematologic: Neutropenic fever, hemorrhage, neutropenic infection 
Hepatic: AST increased, ascites and/or jaundice 
Respiratory: Pneumonia 
Rare known potential toxicities, <1% (Limited to important or life-threatening): 
ALT increased, amylase increased, anaphylactoid reaction, anaphylaxis, angina, arterial 
thrombosis, bleeding, Bradycardia, cardiac arrest, cerebral infarct, cerebrovascular accident, 
circulatory failure, colitis, deep thrombophlebitis, dysrhythmia, embolus, gastrointestinal 
bleeding, gastrointestinal obstruction, hepatomegaly, hiccups, hyperglycemia, hypersensitivity, 
hyponatremia, ileus, interstitial lung disease, intestinal perforation, ischemic colitis, lipase 
increased, lymphocytopenia, megacolon, MI, muscle cramps, myocardial ischemia, pancreatitis, 
paresthesia, peripheral vascular disorder, pulmonary embolus, pulmonary toxicity (dyspnea, 
fever, reticulnodular infiltrates on chest x-ray), renal failure (acute), renal impairment, syncope, 
thrombophlebitis, thrombosis, typhlitis, ulceration, ulcerative colitis, vertigo 
Nursing Guidelines 
If possible, check for any history of hypersensitivity reaction to any previous drug formulated 
with polysorbate 80. 
Cholinergic symptoms of lacrimation, nasal congestion, diaphoresis, flushing, ABD cramping, 
and diarrhea can occur at the beginning, during, or immediately after the irinotecan infusion. It 
is suggested that the patient remain in the treatment area for a minimum of one hour following 
the completion of the very first irinotecan infusion. If diarrhea occurs within one hour of 
infusion, refer to Section 8.1.5 for management. 

Alliance A021703 
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Update #02
 
 
 
Patient education is extremely important. Impress on the patient the importance of compliance 
with treatment of diarrhea management. Stress the need for prompt recognition and early 
intervention. Motivate the patient to report any complications immediately. The cholera-like 
syndrome can be unresponsive to conventional antidiarrheals and can result in severe 
dehydration. 
Ondansetron 
and 
diphenhydramine 
should 
provide 
good 
relief 
from 
the 
nausea/vomiting/cramping. Avoid prochlorperazine on the day of treatment due to its 
association with akathisia (motor restlessness). Prochlorperazine may be taken between 
treatments. 
Advise avoidance of excess caffeine, a GI stimulant. Avoid magnesium-based antacids such as 
Mylanta, Maalox, Rolaids, MOM, Mag-Ox 400, and Tylenol with antacid. 
The pulmonary toxicity seen is usually manifested by dyspnea beginning 42-175 days after 
treatment and occurs at a cumulative dose ranging from 400-1000 mg/m2 (median 750). Instruct 
patient to report any cough or SOB. 
Patients are at risk for developing eosinophilia and will improve on steroid therapy. 
Hepatic enzyme elevations have been transient and did not require intervention. 
Monitor CBC closely. Leukopenia occurs primarily as neutropenia but can be severe and dose 
limiting. The simultaneous occurrence of grade 4 diarrhea and grade 4 neutropenia is rare but 
may render the patient more susceptible to polymicrobial sepsis and potentially death. 
Advise patients of probable hair loss. 
10.7 
Bevacizumab (NSC# 704865) 
Procurement 
Commercial supplies. Institutional pharmacy shall obtain supplies from normal commercial 
supply chain or wholesaler. 
Formulation 
Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody, consisting of 93% 
human and 7% murine amino acid sequences. The agent is composed of human IgG framework 
and murine antigen-binding complementarity-determining regions. Bevacizumab blocks the 
binding of VEGF to its receptors resulting in inhibition of angiogenesis. 
Bevacizumab is commercially available in 100 mg or 400 mg vials (25 mg/mL). 
Bevacizumab or an FDA-approved biosimilar to bevacizumab is allowed. 
Storage and Stability 
Bevacizumab should be stored in a refrigerator (2⁰C to 8⁰C) and should remain refrigerated until 
just prior to use. Do not freeze. Do not shake. The sterile single use vials contain no antibacterial 
preservatives; therefore, vials should be discarded eight hours after initial entry. Solutions 
diluted for infusion may be stored in the refrigerator for up to 8 hours. 
Preparation 
The calculated dose should be diluted in 100 mL of 0.9% Sodium Chloride for Injection. 
Administration 
Bevacizumab is administered as an intravenous infusion as outlined in Section 7.0. The initial 
dose can be administered over a minimum of 90 minutes. If no adverse reactions occur after the 

Alliance A021703 
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Update #02
 
 
 
initial dose, the second dose can be administered over a minimum of 60 minutes. If no adverse 
reactions occur after the second dose, all subsequent doses can be administered over a minimum 
of 30 minutes. If infusion-related adverse reactions occur, all subsequent infusions can be 
administered over the shortest period that was well tolerated. 
Drug Interactions 
DIC has been described in a few patients receiving bevacizumab in combination with 
oxaliplatin, fluorouracil and leucovorin. 
When combined with chemotherapy, bevacizumab is reported to increase the risk of neutropenia 
over that of chemotherapy alone. 
Adverse Events 
Consult the package insert for the most current and complete information. 
According to the package information for bevacizumab, the most serious adverse events 
associated with bevacizumab to date are gastrointestinal perforations/wound healing 
complications, hemorrhage, arterial thromboembolic events, hypertensive crises, nephrotic 
syndrome, and congestive heart failure.  
Hypertension is among the most common adverse events associated with bevacizumab; both 
new hypertension and worsening of existing hypertension have been reported. Hypertensive 
crises have been reported in several studies, and the end organ consequences included CNS 
bleeding and ischemia, and congestive heart failure 
Proteinuria, ranging from asymptomatic abnormal urinalysis to nephrotic syndrome, has been 
described in 10% or more of patients receiving bevacizumab. 
Bleeding, including fatal CNS hemorrhage, has been reported. Bleeding at tumor sites or at sites 
of other pre-existing abnormalities (e.g., diverticulosis, hemorrhoids) has also been described. 
In a phase III study, fatal hemoptysis occurred in 2 of 55 patients with non-small cell lung 
cancer, both of whom had a history of hemoptysis. The rate of fatal hemoptysis in non-squamous 
NSCLC is estimated at 1-2%. Epistaxis is usually short lived and resolves without treatment, 
although some episodes may require medical intervention. 
Thrombosis/embolism; both arterial and venous thromboses (including pulmonary embolism, 
mesenteric vein thrombosis, ischemic bowel, cerebral vascular accident), and myocardial 
infarction have been described in patients receiving bevacizumab. Fatal pulmonary embolus has 
also been described.  
With regard to arterial thromboses (which include myocardial infarction, transient ischemic 
attack, cerebrovascular accident/stroke, and angina/unstable angina), recent studies indicate that 
the risk with bevacizumab and chemotherapy is 2-3 times (up to 5%) that of chemotherapy 
alone. Furthermore, certain baseline characteristics, specifically age > 65 years and prior 
thromboembolic event, conferred additional risk. 
Hepatic Dysfunction: Reversible and marked elevations of liver function tests (total bilirubin 
and/or transaminase and AP) have been rarely reported when bevacizumab is used in 
combination with chemotherapy or concurrently with other drugs that are potentially 
hepatotoxic. The mechanism of such hepatic toxicities is unclear. It is possible that on rare 
occasions, bevacizumab may potentiate the liver side effect of a concurrent medication, although 
it is unclear at this time whether bevacizumab alone can cause LFT derangement. 
Bowel perforation and bowel anastomotic dehiscence have been reported in clinical trials using 
bevacizumab alone or in combination with chemotherapy. Although these events were also 
related to co-existing factors such as tumor involvement, chemotherapy, recent invasive 

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procedures or bowel inflammation, they have occurred at an increased rate in patients receiving 
bevacizumab. A fatal bowel perforation has been described. GI perforation should be included 
in the differential diagnosis of patients receiving bevacizumab therapy presenting with 
abdominal pain or rectal/abdominal abscess. Partial delay in wound healing has been 
demonstrated in animal models treated with anti-VEGF antibodies and it is possible that 
bevacizumab may delay or compromise wound healing in patients. 
Reversible posterior leukoencephalopathy syndrome (RPLS) or similar leukoencephalopathy 
syndrome: RPLS or clinical syndromes related to vasogenic edema of the white matter have 
been recently reported in association with bevacizumab therapy. These syndromes have been 
seen in < 1% of patients to date. Clinical presentations are variable and may include altered 
mental status, seizure and cortical visual deficit. HTN is a common risk factor and was present 
in most (though not all) patients on bevacizumab who developed RPLS. MRI scans are key to 
diagnosis and typically demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images 
and hypointensity in T1 images) predominantly in the white matter of the posterior parietal and 
occipital lobes; less frequently, the anterior distributions and the gray matter may also be 
involved. RPLS should be in the differential diagnosis in patients presenting with unexplained 
mental status change, visual disturbance, seizure or other CNS findings. RPLS is potentially 
reversible, but timely correction of the underlying causes, including control of BP and 
interruption of the offending drug, is important in order to prevent progression to irreversible 
tissue damage. 
Infusion reactions, including fever, chills, rigors, rash, urticaria, dyspnea, and hypersensitivity 
reactions have been reported in approximately 3% of patients. 
Neutropenia: Grade 3-4 neutropenia, febrile neutropenia, or increased rate of infection were 
increased in studies in which bevacizumab with chemotherapy (IFL, paclitaxel and carboplatin) 
was compared to chemotherapy alone. 
Other toxicities: Other reported or potential toxicities associated with bevacizumab include:  
• 
Constitutional—Headache, infection without neutropenia, asthenia 
• 
Cardiovascular—Hypotension, pericardial effusion, congestive heart failure 
• 
Skin—Rash, urticaria 
• 
Gastrointestinal—Nausea, 
vomiting, 
stomatitis/pharyngitis, 
colitis, 
intestinal 
obstruction 
• 
Pulmonary—Pulmonary infiltration, dyspnea 
• 
Musculoskeletal—Arthralgia, chest pain 
11.0 MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1).  
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the short 
axis measurements in the case of lymph nodes are used in the RECIST guideline [26]. 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 8 weeks (i.e. every 4 cycles). 
Supporting documentation of response should be submitted per Section 6.1.5, and radiologic 
images and local interpretation reports should be submitted per Section 6.3. 

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11.2 
Definitions of Measurable and Non-measurable Disease 
11.2.1 Measurable Disease 
A non-nodal lesion is considered measurable if its longest diameter can be accurately 
measured as ≥ 2.0 cm with chest x-ray, or as ≥ 1.0 cm with CT scan or MRI.  
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in diameter 
as assessed using calipers (e.g. skin nodules) on imaging. In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
A malignant lymph node is considered measurable if its short axis is ≥ 1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). 
Tumor lesions in a previously irradiated area are considered measurable disease if there 
has been evidence of disease progression in the previously irradiated area in the 6 months 
prior to registration. 
11.2.2 Non-measurable Disease 
Non-measurable disease includes disease smaller than these dimensions or lesions 
considered truly non-measurable including: leptomeningeal disease, ascites, pleural or 
pericardial effusion, lymphangitic involvement of skin or lung. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods 
All measurements should be recorded in metric notation (i.e. decimal fractions of 
centimeters) using a ruler or calipers. 
The same method of assessment and the same technique must be used to characterize each 
identified and reported lesion at baseline and during restaging. For patients having only 
lesions measuring at least 1 cm to less than 2 cm must use CT imaging for both pre- and 
post-treatment tumor assessments. 
Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used at the same evaluation to assess the antitumor effect of a treatment. 
11.3.2 Acceptable Modalities for Measurable Disease 
• 
Conventional CT and MRI: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. 
o As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease. The lesions should be measured on the same pulse 
sequence. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
11.3.3 Measurement at Follow-up Evaluation 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 

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Cytologic and histologic techniques can be used to differentiate between PR and CR in rare 
cases (e.g. residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain). 
11.4 
Measurement of Treatment/Intervention Effect 
11.4.1 Target Lesions & Target Lymph Nodes 
Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and recorded 
and measured at baseline. These lesions can be non-nodal or nodal (as defined in Section 
11.2.1), where no more than 2 lesions are from the same organ and no more than 2 
malignant nodal lesions are selected.  
Note: If fewer than 5 target lesions and target lymph nodes are identified (as there often 
will be), there is no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions. 
Target lesions and target lymph nodes should be selected on the basis of their size, be 
representative of all involved sites of disease, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on occasion, 
the largest lesion (or malignant lymph node) does not lend itself to reproducible 
measurements in which circumstance the next largest lesion (or malignant lymph node) 
which can be measured reproducibly should be selected. 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target lesions 
plus the sum of the short axis of all the target lymph nodes will be calculated and reported 
as the baseline sum of dimensions (BSD). The BSD will be used as reference to further 
characterize any objective tumor response in the measurable dimension of the disease. 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will be calculated 
and reported as the post-baseline sum of dimensions (PBSD). If the radiologist is able to 
provide an actual measure for the target lesion (or target lymph node), that should be 
recorded, even if it is below 0.5 cm. If the target lesion (or target lymph node) is believed 
to be present and is faintly seen but too small to measure, a default value of 0.5 cm should 
be assigned. If it is the opinion of the radiologist that the target lesion or target lymph node 
has likely disappeared, the measurement should be recorded as 0 cm. 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the PBSD. 
11.4.2 Non-target Lesions & Non-target Lymph Nodes 
Non-measurable sites of disease are classified as non- target lesions or non-target lymph 
nodes and should also be recorded at baseline. These lesions and lymph nodes should be 
followed in accord with Section 11.4.3. 
11.4.3 Response Criteria 
All target lesions and target lymph nodes followed by CT/MRI must be measured on re-
evaluation at evaluation times specified in Section 11.1. Specifically, a change in objective 
status to either a PR or CR cannot be done without re-measuring target lesions and target 
lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. In selected 
circumstances, certain non-target organs may be evaluated less frequently. For example, 

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bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
• 
Evaluation of Target Lesions 
o Complete Response (CR): All of the following must be true: 
▪ 
Disappearance of all target lesions. 
▪ 
Each target lymph node must have reduction in short axis to < 1.0 
cm. 
o Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis of all 
the target lymph nodes at current evaluation) taking as reference the BSD 
(see Section 11.4.1). 
o Progression (PD): At least one of the following must be true: 
▪ 
At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during follow-up. 
▪ 
At least a 20% increase in PBSD (sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target 
lymph nodes at current evaluation) taking as reference the MSD 
(see Section 11.4.1). In addition, the PBSD must also demonstrate 
an absolute increase of at least 0.5 cm from the MSD. 
o Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
• 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
o Complete Response (CR): All of the following must be true: 
▪ 
Disappearance of all non-target lesions. 
▪ 
Each non-target lymph node must have a reduction in short axis 
to < 1.0 cm. 
o Non-CR/Non-PD: Persistence of one or more non-target lesions or non-
target lymph nodes 
o Progression (PD): At least one of the following must be true: 
▪ 
At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during follow-up. 
▪ 
Unequivocal progression of existing non-target lesions and non-
target lymph nodes. (NOTE: Unequivocal progression should not 
normally trump target lesion and target lymph node status. It must 
be representative of overall disease status change.) 
11.4.4 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, 
and new disease as defined in the following table:  

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For Patients with Measurable Disease 
Target Lesions & 
Target Lymph Nodes 
Nontarget Lesions & 
Nontarget Lymph Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated (NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
* 
See Section 11.4.3 
11.4.5 Symptomatic Deterioration 
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time, and not either related to 
study treatment or other medical conditions, should be reported as “symptomatic 
deterioration” on the corresponding Case Report Form in Rave. Every effort should be 
made to document the objective progression even after discontinuation of treatment due to 
symptomatic deterioration, and radiologic imaging should continue to be collected every 
8-16 weeks (+/- 1 week)  until disease progression (or start of a new anticancer therapy); 
see Section 5.0. 
11.5 
Definitions of Analysis Variables 
Formal definitions of variables used in analyses can be found in the Statistical Considerations 
section (Section 13.0) of the protocol. 

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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Protocol Treatment  
Protocol treatment (intervention) is to continue until one of the criterion for discontinuation 
listed below has been met. Please see the study calendar (Section 5.0) and the treatment section 
(Section 7.0) for treatment and following up time periods. 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Disease progression per RECIST v1.1 
• 
Clinical progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the protocol treatment 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
• 
Surgical intervention, radiotherapy, cryotherapy, ablation, etc. is performed on the 
primary neoplasm or metastasis 
• 
Patient is five (5) years from registration/randomization 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
12.3 
Follow-up  
12.3.1 Duration of Follow-up  
Participants will be followed for 5 years from the date of registration/randomization or 
until death, whichever occurs first. 
12.3.2 Follow-up for Patients who Stop Study Treatment Early  
All participants who discontinued study treatment for any reason other than disease 
progression and all participants whose tumor progression was not documented at the end-
of-study visit will continue to have tumor assessments every 8-16 weeks (+/- 7 days) until 
documented disease progression or until the start of additional anti-tumor therapy. 

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12.3.3 Follow-up for Specimen Submission 
If the patient discontinues study treatment for any reason, specimens should continue to be 
collected and submitted after discontinuation of therapy per Section 6.2. 
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
12.5 
Managing Ineligible Patients and Registered Patients Who Never Receive Protocol 
Intervention  
Definition of ineligible patient 
A study participant who is registered to the trial but does not meet all of the eligibility criteria 
is deemed to be ineligible.  
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided 
the treating physician, study chair, and executive officer agree there are no safety concerns if 
the patient continues protocol treatment. All scans, tests, and data submission are to continue as 
if the patient were eligible. Notification of the local IRB may be necessary per local IRB 
policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for 
those patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), the follow-up requirements are specified below.  
Baseline, off treatment, and post-treatment follow up (i.e., relapse, progression, and survival) 
data submission required. See the Data Submission Schedule accompanying the All Forms 
Packet. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This randomized phase III trial is designed to compare progression-free survival of patients with 
previously untreated metastatic colorectal cancer who receive either 1) high-dose vitamin D3 in 
combination with standard chemotherapy (FOLFOX or FOLFIRI) + bevacizumab or 2) 
standard-dose vitamin D3 in combination with standard chemotherapy (FOLFOX or FOLFIRI) 
+ bevacizumab. Patients will be randomized in a 1:1 allocation to either arm. One interim 
analysis for futility will be performed. It will allow stopping early for futility while controlling 
overall alpha level. The sample size calculation was conducted using EAST v6.4. 
Efficacy analyses will be based on the intent to treat principle. Any analyses related to adverse 
events will be based on the safety population. All patients who were randomized and received 

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any amount of protocol therapy will be considered part of the safety population and evaluable 
for safety analysis. For the purposes of safety analysis, patients will be assigned to the treatment 
group for the therapy that was actually received. 
13.2 
Statistical Design and Analysis for the Primary Endpoint 
13.2.1 Primary Endpoint 
The primary endpoint of this study is progression-free survival (PFS). PFS is defined as 
the time from randomization to the first documentation of disease progression (per RECIST 
v1.1) or death. The censoring rule is as follows: 
• 
Patients who are still alive and have not progressed will be censored for PFS at the 
time of their last disease assessment.  
• 
Patients who initiate alternative (new) anti-cancer therapy will be censored for PFS 
at the time of their last disease assessment prior to initiation of alternative (new) 
anti-cancer therapy. 
• 
Patients who are alive and have no tumor measurement post-baseline will be 
censored for PFS at Day 1 post-randomization.  
Efficacy analyses will be based on the intent-to-treat principle. All randomized patients 
regardless of whether any treatment is received will be included in the analysis. Patients 
will be assigned to the treatment group they were randomized to regardless of actual 
treatment received. 
13.2.2 Statistical Design 
Based on the results from CALGB 80405, we anticipate a PFS median of approximately 
10 months [27]. We plan to accrue a total of 445 patients (approximately 222 patients per 
arm) in 39 months with a minimum follow-up of 13 months to achieve 273 PFS events. 
The length of accrual time is based on an accrual rate of 3 patients per month for the first 
6 months, 12 patients per month for 1 year (after the first 6 months) and 14 patients per 
month for the remaining accrual period. This design with one interim analysis for futility 
only with O’Brien-Fleming type stopping boundary (Gamma family with parameter -4 for 
futility) will yield 90% power to detect a hazard ratio of 0.70 (median PFS of 10 vs. 14.3 
months) assuming exponential survival and using a one-sided log-rank test with type I error 
rate of 0.05. This sample size takes into account a 27.6% drop-out rate due to patients 
coming off treatment for reasons other than disease progression (.e.g. surgical resection). 
The sample size is increased from the original 400 to 445, in Update #03, due to a higher 
than expected drop-out rate observed. 
13.2.3 Study Operating Characteristics 
The table below shows the operating characteristics assuming the PFS follows exponential 
survival functions. The percent of times that 1) the study would stop early due to futility 
and 2) the study would conclude that high-dose vitamin D3 + (FOLFOX or FOLFIRI) + 
bevacizumab is superior to standard dose vitamin D3 + (FOLFOX or FOLFIRI) + 
bevacizumab at the final analysis are tabulated by true medians of PFS and the true hazard 
ratio. Proportions are based on 10,000 replicates in the simulation study. 
True Median PFS (Months) 
True 
hazard 
ratio 
% of times 
the study will 
be stopped 
% of times that standard-
dose vitamin D3 + 
(FOLFOX or FOLFIRI) + 
Standard-dose 
vitamin D3 + 
(FOLFOX or 
High-dose 
vitamin D3 + 
(FOLFOX or 

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FOLFIRI) + 
bevacizumab 
FOLFIRI) + 
bevacizumab 
early for 
futility 
bevacizumab is superior at 
the final analysis 
10.0 
14.29 
0.70 
1.12 
89.84 
10.0 
13.22 
0.756 
3.54 
74.64 
10.0 
12.15 
0.823 
9.47 
48.76 
10.0 
11.07 
0.903 
21.74 
21.0 
10.0 
10.0 
1.00 
41.99 
4.9 
13.2.4 Analysis Plan 
Interim Analysis Decision Rules 
One interim analysis will be performed to assess treatment futility and will be performed 
at the time at which 50% of the projected PFS events (137 PFS events) have occurred. The 
specific hazard ratios and critical p-values for declaring futility at the interim analysis is 
specified in the table below. When PFS crosses futility boundary, the accrual will be 
suspended (if still ongoing), the currently enrolled patients will be followed per protocol, 
and the data will be reported. 
Analysis time 
point (% events) 
Number of 
PFS events 
Critical p-value 
for futility 
HR for 
futility 
50% 
137 
>0.568 
>1.03 
Final Analysis Decision Rules 
The primary efficacy analysis will be performed at the time when 273 PFS events have 
occurred. The specific hazard ratio and critical p-values for declaring superiority or futility 
are specified in the table below. Specifically, at the final analysis, if p-value is less than or 
equal to 0.05 the high-dose vitamin D3 + (FOLFOX or FOLFIRI) + bevacizumab regimen 
will be deemed effective; otherwise, high-dose vitamin D3 + (FOLFOX or FOLFIRI) + 
bevacizumab regimen will be considered to have not met the criteria for efficacy. 
Analysis time 
point (% events) 
Number of 
PFS events 
Critical p-value 
for efficacy 
HR for 
efficacy 
Critical p-value 
for futility 
HR for 
futility 
100% (Final) 
273 
0.05 
0.819 
0.05 
0.819 
Analysis Plan for Both Interim and Final Analyses: PFS will be compared between 
treatment arms using the un-stratified log-rank test and its one-sided p-value will be used 
for decision making. The HR for PFS will be estimated using a Cox proportional hazards 
model and the 95% CI for the HR will be provided. Results from a stratified analysis will 
also be provided. Kaplan-Meier methodology will be used to estimate the median PFS for 
each treatment arm, and Kaplan-Meier curves will be produced. Brookmeyer-Crowley 
methodology will be used to construct the 95% CI for the median PFS for each treatment 
arm 28. A sensitivity analysis of PFS comparison across arms will be conducted where PFS 
will be censored at surgery date for patients who receive surgery with curative intent. 
Comparison of PFS across arms while adjusting for baseline characteristics will also be 
conducted as an exploratory analysis. 

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13.3 
Sample Size, Accrual Time, and Study Duration 
13.3.1 Sample Size 
We anticipate randomizing a maximum of 445 patients (approximately 222 per arm) per 
statistical design in Section 13.2. 
13.3.2 Accrual Rate and Accrual Duration 
CALGB 80405 accrued approximately 30 patients per month. For this protocol, MSI-high 
patients will be excluded (approximately 5% prevalence rate). Thus, the accrual rate is 
projected to be approximately 28 patients per month. We made the same assumption for 
the accrual rate for the original study design. In Update #03 where the sample size was 
increased to 445, we updated the accrual rate by using three different accrual periods in 
which the rate in each period is approximately the actual observed accrual rate in the study 
(see Section 13.2.2). Accrual will not be halted for interim analysis. We anticipate that the 
study will take approximately 39 months to fully accrue if there are no major issues of 
patient safety and the study passes interim analysis. 
13.3.3 Primary Endpoint Completion Date for ClinicalTrials.gov Reporting 
For purpose of ClinicalTrials.gov reporting, the primary endpoint completion date (PECD) 
for this study is the time the 273rd PFS event occurs. Per design, the maximum study 
duration is estimated to be 52 months (39-month accrual time + 13 month follow-up) from 
the first patient randomized. 
13.4 
Supplementary Analysis Plans 
13.4.1 Secondary Endpoints 
• 
Objective Response: Unconfirmed objective response by RECIST v1.1 criteria 
will be estimated using objective response rate (ORR) where ORR is defined as 
the number of evaluable patients achieving a response (PR or CR per RECIST 
v1.1) during treatment with study therapy divided by the total number of evaluable 
patients. The population of evaluable patients for this analysis will be the same as 
the ITT population defined above. Rates of response will be compared across arms 
using a Chi-Square Test for Proportion. Point estimates will be generated for 
objective response rates within each arm along with 95% binomial confidence 
intervals [29]. 
• 
Overall Survival: Overall survival time is defined as the time from randomization 
to death due to any cause. Patients who are alive will be censored at last follow-up 
for overall survival. The distribution of survival time will be estimated using the 
method of Kaplan-Meier [30]. Overall survival will be compared between 
treatment arms using the log-rank test. OS medians, survival rates at 3 years and 
HR will be estimated along with 95% confidence intervals. 
• 
Adverse Event: Adverse events will be evaluated via the  CTCAE standard 
toxicity grading. Overall adverse event profiles by treatment arm will be explored 
and summarized. Frequency distributions, graphical techniques, and other 
descriptive measures will form the basis of the analysis. 
• 
Physical Activity & PFS: PFS of patients receiving high-dose vitamin D3 vs. 
patients receiving standard-dose vitamin D3 will be compared in subgroups of 
physical activity (PA) levels. The levels will be defined as low PA (< 9 metabolic-
equivalent task [MET]-hours/week) vs. high PA (≥ 9 MET-hours/week). The 
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within each subgroup and arm combination [30]. PFS will be compared between 
treatment arms using the non-stratified log-rank test in each subgroup of PA levels. 
PFS medians, survival rates at 3 years, and HR will be estimated along with 95% 
confidence intervals within each subgroup and arm combination. Interaction 
between PA subgroups and treatment arms will be tested using likelihood ratio 
test. 
• 
Baseline Prevalence of Vitamin D3 Deficiency: The baseline prevalence of 
vitamin D3 deficiency will be defined as the number of evaluable vitamin D3 
deficient patients divided by the total number of evaluable patients. The population 
of evaluable patients for this analysis will be all patients whose 25(OH)D level was 
successfully measured at baseline. Vitamin D3 deficiency is defined as 25(OH)D 
level < 20 ng/mL. Prevalence of vitamin D3 deficiency will be compared across 
arms using a Chi-Square Test for Proportion. Point estimates will be generated for 
vitamin D3 deficiency rates within each arm along with 95% confidence intervals 
[29]. 
• 
Subgroup Analyses for PFS: PFS of patients receiving high-dose vitamin D3 vs. 
patients receiving standard-dose vitamin D3 will be compared in subgroups of 
baseline 25(OH)D levels, baseline demographic and clinicopathologic factors 
(e.g., body mass index [<25 vs 25-30 vs. ≥30 kg/m2], presence of liver metastases 
[yes vs. no], RAS mutation status [wildtype vs. mutant]). Baseline 25(OH)D levels 
will be defined as deficient (< 20 ng/mL) vs. other (≥ 20 ng/mL). The distribution 
of PFS time will be estimated using the method of Kaplan-Meier within each 
subgroup and arm combination [30]. PFS will be compared between treatment 
arms using the non-stratified log-rank test in each subgroup  PFS medians, survival 
rates at 3 years, and HR will be estimated along with 95% confidence intervals 
within each subgroup and arm combination. Interaction between  subgroups and 
treatment arms will be tested using likelihood ratio test. Comparison of PFS across 
arm in subgroups of interest while adjusting for baseline characteristics will also 
be conducted as exploratory analysis. 
• 
Prognostic Effect of Highest Achieved 25(OH)D & PFS: PFS of patients will 
be compared in subgroups of highest achieved 25(OH)D levels. The levels will be 
defined by quartile of highest-achieved level among patients who have both 
baseline and at least one on-treatment 25(OH)D sample result. The distribution of 
PFS time will be estimated using the method of Kaplan-Meier within each 
subgroup [30]. PFS will be compared across quartiles using the non-stratified log-
rank test. PFS medians, survival rates at 3 years, and HR will be estimated along 
with 95% confidence intervals. Baseline 25(OH)D will be entered into the Cox 
model as a covariate. 
13.5 
Monitoring the Study 
13.5.1 Adverse Event Stopping Rule 
The Study Chair and A021703 Statistician will review the accrual and safety data 
periodically, as well as the Alliance Group Meeting Reports, in order to identify any 
feasibility problems associated with accrual rates and adverse events. There is no formal 
adverse event stopping rule for this study. 

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13.5.2 Accrual Monitoring Stopping Rule 
The NCI Cancer Therapy Evaluation Program (CTEP) accrual guidelines for phase III 
trials will be utilized for this study. The current guidelines can be found on the CTEP 
website
  
13.6 
Study Reporting 
Data Safety Monitoring Board Reporting 
This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an NCI-
approved functioning body. Reports containing efficacy, adverse event, and administrative 
information will be provided to the DSMB every six months as per NCI guidelines. 
Clinical Data Update System Reporting 
This study will be monitored by the Clinical Data Update System (CDUS) version 2.0. An 
abbreviated report containing cumulative CDUS data will be submitted quarterly to CTEP by 
electronic means. Reporting time points are: January 31, April 30, July 31, and October 31. 
13.7 
Descriptive Factors 
• 
Tumor Biology: Metachronous, Synchronous vs. Unknown 
• 
Primary Tumor Unresected at Study Entry: Yes vs. No 
• 
Disease Description: Locally Advanced vs. Metastatic 
• 
Metastatic Sites: Local lymph node vs. Distant lymph node vs. Liver vs. Abdominal 
wall vs. Bone vs. CNS/brain vs. Lung vs. Pelvis vs. Peritoneum vs. others  
13.8 
Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. 
There is no information currently available regarding differential effects of this regimen in 
subsets defined by race, gender, or ethnicity, and there is no reason to expect such differences 
to exist. Therefore, although the planned analysis will, as always, look for differences in 
treatment effect based on racial and gender groupings, the sample size is not increased in order 
to provide additional power for subset analyses. 
The geographical region served by the Alliance, has a population which includes approximately 
18% minorities. Based on prior Alliance studies involving similar disease sites, we expect about 
15% of patients will be classified as minorities by race and about 38.75% of patients will be 
women. Expected sizes of racial by gender subsets for patients registered randomized to this 
study are shown in the following table. 
 
 
 

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DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
1 
1 
 
 
2 
Asian 
6 
7 
 
 
13 
Native Hawaiian 
or Other Pacific 
Islander 
1 
1 
 
 
2 
Black or African 
American 
19 
31 
 
 
50 
White 
135 
215 
10 
16 
376 
More Than One 
Race 
 
 
1 
1 
2 
Total 
162 
255 
11 
17 
445 
 
14.0 CORRELATIVE AND COMPANION STUDIES  
There will be a mandatory retrospective diet and lifestyle impact analysis, a mandatory retrospective 
plasma 25(OH)D level analysis, and optional biobanking for future correlative science studies, and 
all patients are encouraged (or required) to participate.  
14.1 
Diet and Lifestyle Questionnaire Analysis 
14.1.1 Background 
Epidemiologic and scientific research indicates that diet and other lifestyle factors have a 
significant influence on the risk of developing colorectal cancer. Consumption of red meat, 
alcohol, calcium, fiber, aspirin, folic acid, obesity, physical activity, and cigarette smoking 
are among factors that have been suggested to influence the risk of developing colorectal 
cancer [31-51]. 
Not until recently have there been data assessing the influence of these factors on treatment 
outcomes and survival in patients with established cancer. In CALGB 80405 (trial of either 
bevacizumab or cetuximab with chemotherapy [FOLFOX or FOLFIRI] for stage IV colon 
cancer), a self-completed questionnaire was utilized to assess diet, physical activity, 
smoking, medication use and family history. Multiple important findings have stemmed 
from this trial. However, these data were collected over a decade ago; dietary intake and 
physical activity patterns may have changed since then. Therefore, it is important to collect 
contemporary data on dietary intake, physical activity, and other modifiable factors in this 
study to investigate the impact of these variables on clinical outcomes. 
14.1.2 Objectives 
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. 
14.1.3 Methods 
In this companion study, patients participating in the treatment trial will be asked to 
complete a 131-item validated, food-frequency questionnaire within first 6 weeks of 

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randomization. The questionnaire, designed by Dr. Walter Willett and colleagues for the 
Nurses’ Health Study, has been extensively validated among both health professional and 
lay populations, and provides comprehensive data on over 100 micro-nutrients, with and 
without supplement use. This questionnaire can be self-administered. Within the 
questionnaire, a series of questions about leisure-time physical activity, smoking habits, 
alcohol intake, and other habits that have also been validated in large populations will be 
included. Height and weight will also be obtained as part of the clinical trial. A similar 
study was initiated in the preceding CALGB first-line metastatic trial (CALGB 80405) and 
more than 65% of eligible patients completed the questionnaire. 
Validation of the Semi-quantitative Food Frequency Questionnaire (SFFQ): The 
current version of the questionnaire consists of 131 food items plus vitamin and mineral 
supplement use that collectively account for over 90% of the intake of the nutrients 
assessed [52-56]. For each food, a commonly used unit or portion size (e.g. one egg or slice 
of bread) is specified, and participants are asked how often, on average over the past year, 
they consumed that amount of each food. There are nine possible responses which range 
from never to six or more times per day. The nutrient intakes will be computed by 
multiplying the frequency of consumption of each food by the nutrient content of the 
specified portions, using composition values from Department of Agriculture sources 
supplemented with other data, including the components of specific vitamins and breakfast 
cereals. All nutrients will be adjusted for total energy intake by the residuals method [57]. 
In 1980, the food frequency questionnaire was administered twice to 173 individuals at an 
interval of approximately one year, and four one-week diet records for each subject were 
collected during that period. Diet records probably are the best measures of current, short-
term food intake. Since the seven-day record provides information for a relatively short 
period of time, four one-week diet records in different seasons were collected. The mean 
calorie adjusted intakes from the four one-week diet records and those from the 
questionnaire were well-correlated [54-56]. In the 1986 diet validation study, the 
correlation between folate calculated from the SFFQ and red cell folate level was 0.55 [34]. 
Nutrients calculated from the expanded SFFQ were correlated with other corresponding 
biochemical indicators: plasma beta-carotene (r = 0.30-0.42), plasma vitamin E (r = 0.41-
0.53), adipose linoleic acid (r = 0.35-0.37), adipose trans fatty acid (r = 0.51), and adipose 
N-3 fatty acids (r = 0.48-0.49) [58-61]. To evaluate further the capability of the revised 
131-item questionnaire to discriminate among subjects, Willett and colleagues asked 127 
individuals to complete two weeks of diet records and the semi-quantitative food frequency 
questionnaire in 1986. The mean calorie adjusted intakes from the diet records and those 
from the questionnaire were well-correlated [54]. 
The validity of this 131-item SFFQ was be separately assessed in 200 patients with 
colorectal, breast, or neuroendocrine cancer undergoing treatment with cytotoxic 
chemotherapy [62]. The Pearson correlation coefficients for various carotenoids as 
measured by the questionnaire, with the corresponding measurements in plasma 
specimens, ranged from 0.33 to 0.44 (all P < .001), adjusted for total energy intake, body 
mass index, age, sex, smoking status, and total plasma cholesterol. Similarly, the adjusted 
correlation between self-reported total vitamin E intake and plasma alpha-tocopherol was 
0.34 (P < .001). Correlations between questionnaire and plasma measurements of trans-fat, 
eicosapentaenoic acid, and docosahexaenoic acid were 0.55, 0.29, and 0.42 (all P < .001), 
respectively. These levels of correlation were consistent with those reported in similar 
studies of self-reported diet in otherwise healthy populations. Thus, among patients with 
cancer receiving cytotoxic chemotherapy, questionnaire-based measurements of various 

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micronutrients and dietary factors appeared to predict meaningful differences in the 
corresponding measurements in plasma specimens. 
These data indicate that the proposed self-administered dietary questionnaires provide 
highly informative and biologically relevant measurement of a wide variety of nutrients, 
thus allowing one to address the dietary hypotheses outlined in the specific aims. 
In terms of other measures from the survey, Wolf et al. reported on a detailed validation 
study of the physical activity questionnaire among a sample of 325 participants in the 
Nurses’ Health Study II (NHS II) (241 random cohort sample and 84 random sample of 
African American participants) [63]. Participants completed four 1-week activity recalls 
and four 7-day activity diaries over one year and then repeated the NHS II activity 
questionnaire. For the total activity score, the correlations of the last activity questionnaire 
with the diaries was 0.64 for the total cohort sample and 0.59 for the African American 
sample. Within the Health Professionals Follow-up Study, a parallel study of men, validity 
of the physical activity questionnaire was assessed among 238 randomly selected 
participants by comparisons with four 1-week activity diaries, four 1-week activity recalls, 
and resting and post exercise pulse rates [64]. Correlations with the activity diaries were 
0.41 for inactivity (sitting) and 0.58 for vigorous physical activity. Vigorous activity 
assessed by the questionnaire was correlated with resting pulse (r = -0.45) and post-exercise 
pulse (r = -0.41). 
14.1.4 Statistical Analysis 
The primary efficacy variable for analyses will be progression-free survival (PFS). 
Secondary efficacy endpoint is overall survival (OS). 
Exposure Definitions: For all dietary exposures including dietary and supplemental 
vitamin D3, intakes will be categorized into energy-adjusted quintiles, consistent with our 
previous studies. In addition, physical activity will be categorized into categories of MET-
hours as previously defined in prior work. Body mass index (in kg/m2) will be divided into 
World Health Organization categories of underweight, normal weight, overweight and 
obesity. Baseline characteristics of patients will be compared according to quintiles of the 
biomarker using Wilcoxon signed rank tests for continuous variables and chi-squared tests 
for categorical variables. The log-rank test and Kaplan-Meier curves will be used to 
compare PFS and OS across different covariate level. Cox proportional hazards models 
will be used to control for multiple confounders. The two-tailed P value for the linear trend 
test across categories will be calculated using the exposure level as a continuous variable, 
consistent with prior studies. In secondary analyses, we will examine how the relationship 
between a specific exposure level and patient outcome is modified by relevant covariates 
such as ECOG performance status, treatment assignment, physical activity and body mass 
index, among others. Tests for statistical interaction will be performed by entering into the 
model the cross-product term of the exposure level as a continuous variable with the 
covariate as a continuous or binary variable. 
14.2 
Plasma 25(OH)D Level Analysis 
14.2.1 Background 
Plasma 25(OH)D is considered the best indicator of vitamin D3 status by the institute of 
medicine (IOM) due to its long half-life, lack of feedback regulation of its synthesis, and 
because it reflects all potential sources and precursors of vitamin D3 [65]. Although 
significant dose-response relationships between plasma 25(OH)D and outcome have been 
reported, supporting biologic plausibility, the optimal plasma 25(OH)D concentration 
associated with a survival benefit remains unclear [17, 21]. Moreover, the kinetics of 

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25(OH)D response to oral vitamin D3 in mCRC patients is unknown, and may be affected 
by both known variables relevant to the general population (i.e., skin pigmentation, diet, 
season, adiposity), and issues unique to cancer patients (receipt of chemotherapy has been 
linked to severe vitamin D3 deficiency and attenuated response to supplementation) [66-
70]. In addition, baseline 25(OH)D levels may influence the degree of response to vitamin 
D3, and ample data show that the dose-response relationship is not linear [71, 72]. Indeed, 
in our dose-finding RCT of vitamin D3 in blacks, we confirmed that higher doses resulted 
in higher 25(OH)D levels at three months, and lower baseline 25(OH)D predicted a larger 
increase in 25(OH)D with any given dose of vitamin D3 [73]. In light of the complexity of 
the vitamin D3 dose-response relationship, particularly in cancer patients, it is imperative 
to investigate the impact of vitamin D3 supplementation on 25(OH)D levels in mCRC 
patients within the context of prospective randomized intervention. We therefore propose 
to test the hypothesis that raising 25(OH)D levels with vitamin D3 results in improved 
survival. Moreover, we will also test the distinct hypothesis that lower baseline 25(OH)D 
levels are associated with worse survival, and these deficient patients are most likely to 
benefit from high-dose supplementation. 
14.2.2 Objectives 
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 25(OH)D levels. 
To evaluate the prognostic effect of highest-achieved 25(OH)D levels with PFS. 
14.2.3 Methods 
Plasma 25(OH)D levels will not be checked during the study, but blood will be serially 
collected, processed, and banked at -80ºC per standard procedures for future 25(OH)D 
analysis. Plasma 25(OH)D concentrations will be measured in a single batch at study 
completion by liquid chromatography/mass spectrometry at Heartland Assays Inc. (Ames, 
IA) with 10% blinded quality control (QC) samples interspersed. All laboratory staff will 
be blinded to patient status. The assay is validated as part of the CDC Vitamin D 
Standardization-Certification Program (VDSCP) and the DEQAS proficiency program, 
and it is calibrated to National Institute of Standards and Technology (NIST) reference 
ranges, as previously reported [74]. 
14.2.4 Statistical Analysis 
We will evaluate the relationship between 1) highest-achieved plasma 25(OH)D, and 2) 
baseline 25(OH)D, and PFS and OS using Cox proportional hazards modeling, adjusted 
for assigned treatment arm and relevant clinical and biological. We will calculate P values 
for trend by using 25(OH)D as a continuous variable in the model. We will investigate the 
relationship between vitamin D3 dose and survival within subgroups defined by low vs. 
high baseline plasma 25(OH)D to assess for effect modification. Tests for statistical 
interaction will be performed by entering into the Cox model the cross-product term of 
vitamin D3 dose with continuous baseline 25(OH)D. 
14.3 
Biobanking for Future Correlative Science Studies 
NOTE: Testing of banked samples will not occur until an amendment to this treatment protocol 
(or separate correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 

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Note: All laboratory correlates are classified as exploratory, and the specimens requested for 
submission in Section 6.2 will be collected for banking-only at this time. 
Blood, tissue, and stool specimens will be collected and stored for future translational research 
for patients who consent to participate. Future studies may include: mutation analysis, immune 
cell biomarker studies, ctDNA, inflammation markers/cytokines, pharmacogenetic studies, 
future molecular and immunohistochemical studies, and microbiome profiling from stool 
samples. 
15.0 MONITORING PLAN 
Use standard Alliance monitoring procedures. 
 
 

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Hunter, D.J., et al., Comparison of measures of fatty acid intake by subcutaneous fat aspirate, food 
frequency questionnaire, and diet records in a free-living population of US men. Am J Epidemiol, 
1992. 135(4): p. 418-27. 
61. 
London, S.J., et al., Fatty acid composition of subcutaneous adipose tissue and diet in 
postmenopausal US women. Am J Clin Nutr, 1991. 54(2): p. 340-5. 
62. 
Meyerhardt, J.A., et al., Assessment of a dietary questionnaire in cancer patients receiving 
cytotoxic chemotherapy. J Clin Oncol, 2005. 23(33): p. 8453-60. 
63. 
Wolf, A.M., et al., Reproducibility and validity of a self-administered physical activity 
questionnaire. Int J Epidemiol, 1994. 23(5): p. 991-9. 
64. 
Chasan-Taber, S., et al., Reproducibility and validity of a self-administered physical activity 
questionnaire for male health professionals. Epidemiology, 1996. 7(1): p. 81-6. 
65. 
in Dietary Reference Intakes for Calcium and Vitamin D, A.C. Ross, et al., Editors. 2011: 
Washington (DC). 
66. 
Clemens, T.L., et al., Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. 
Lancet, 1982. 1(8263): p. 74-6. 
67. 
Kull, M., Jr., et al., Seasonal variance of 25-(OH) vitamin D in the general population of Estonia, 
a Northern European country. BMC Public Health, 2009. 9: p. 22. 
68. 
Blum, M., G.E. Dallal, and B. Dawson-Hughes, Body size and serum 25 hydroxy vitamin D 
response to oral supplements in healthy older adults. J Am Coll Nutr, 2008. 27(2): p. 274-9. 

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69. 
Fakih, M.G., et al., Chemotherapy is linked to severe vitamin D deficiency in patients with 
colorectal cancer. Int J Colorectal Dis, 2009. 24(2): p. 219-24. 
70. 
Fakih, M.G., et al., A prospective clinical trial of cholecalciferol 2000 IU/day in colorectal cancer 
patients: evidence of a chemotherapy-response interaction. Anticancer Res, 2012. 32(4): p. 1333-
8. 
71. 
Schwartz, J.B., L. Kane, and D. Bikle, Response of Vitamin D Concentration to Vitamin D3 
Administration in Older Adults without Sun Exposure: A Randomized Double-Blind Trial. J Am 
Geriatr Soc, 2016. 64(1): p. 65-72. 
72. 
Aloia, J.F., et al., Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. 
Am J Clin Nutr, 2008. 87(6): p. 1952-8. 
73. 
Ng, K., et al., Dose response to vitamin D supplementation in African Americans: results of a 4-
arm, randomized, placebo-controlled trial. Am J Clin Nutr, 2014. 99(3): p. 587-98. 
74. 
Makowski, A.J., et al., Simplified 25-Hydroxyvitamin D Standardization and Optimization in Dried 
Blood Spots by LC-MS/MS. J AOAC Int, 2017. 100(5): p. 1328-1336. 
 

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Version Date: 09/20/2022 
 
Update #02
 
 
 
APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS 
 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, completed by the patient, and 
entered into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document. A booklet containing this 
assessment does not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Fatigue 
 
 
 
 
 
 
 
 
Fatigue as bad  
as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as it can be 
 
 
 
 
 
 
 
As good as it can be 
 
 
 
 

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Version Date: 09/20/2022 
 
Update #02
 
 
 
APPENDIX II 
PATIENT MEDICATION DIARY 
  
Patient Initials: __________ Patient ID Number: __________ Study Number: __________ 
Cycle #: _________ 
 
Patient Instructions 
• 
Please fill in on the table below every day that you take your study medication by writing in the 
number of capsules you take, the date and time at which you take them, and any comments 
regarding that day’s dose. 
• 
Please bring these medication log (diary) sheets, the empty pill bottle(s), and any extra vitamin 
D3 capsules with you to all appointments. 
• 
Vitamin D3 should be taken by mouth (orally) with or without food at the same time every day. 
Grapefruit/juice, pomegranate/juice, pomelos, star fruits, and Seville oranges should be avoided 
while on vitamin D3. 
• 
Vitamin D3 can be taken either before or after the usual treatment on days when you receive both. 
• 
For the first cycle of treatment only, you will be given two bottles with capsules that look 
identical, but each bottle will contain a different dose of vitamin D3 or a placebo. You will take 
two vitamin D3 capsules (one from each bottle) by mouth once a day for each day of the first 
cycle. This is called the “loading dose” period. 
• 
If you miss a dose, please take the missed dose as soon as possible, but only if there are 12 or 
more hours remaining before the next scheduled dose. 
• 
If you miss a dose and the next dose is due (scheduled) in less than 12 hours, then place a “0” for 
the “Number of Capsules” you took that day, and do not take the “missed” dose. Please take the 
next dose as scheduled. 
• 
If vomiting occurs after taking vitamin D3, then do NOT take a replacement dose on that day 
(unless it appears that an intact or whole capsule has been vomited). Start taking vitamin D3 
again with the next scheduled dose. If consistent vomiting occurs, please notify your doctor. 
• 
Vitamin D3 capsules should be stored at room temperature; do not crush or chew capsules. 
 
 

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Version Date: 09/20/2022 
 
Update #02
 
 
 
CYCLE #: _______ 
DAY 
MEDICATION 
DATE 
TIME 
NUMBER OF 
CAPSULES TAKEN 
COMMENTS 
Example 
Vitamin D3 
05/01/2019 
9:00 
AM 
1 
None 
1 
Vitamin D3 
 
 
 
 
 
2 
Vitamin D3 
 
 
 
 
 
3 
Vitamin D3 
 
 
 
 
 
4 
Vitamin D3 
 
 
 
 
 
5 
Vitamin D3 
 
 
 
 
 
6 
Vitamin D3 
 
 
 
 
 
7 
Vitamin D3 
 
 
 
 
 
8 
Vitamin D3 
 
 
 
 
 
9 
Vitamin D3 
 
 
 
 
 
10 
Vitamin D3 
 
 
 
 
 
11 
Vitamin D3 
 
 
 
 
 
12 
Vitamin D3 
 
 
 
 
 
13 
Vitamin D3 
 
 
 
 
 
14 
Vitamin D3 
 
 
 
 
 
 
 
Comments: ___________________________________________________________________________ 
 
Patient Signature: _______________________________________________ 
Date: ______________ 
 
 
The table below is to be completed ONLY by Site Staff (Nurse/CRP) after the cycle is completed: 
Pill Bottle Returned (Circle) 
Yes            No 
Date of Pill Count (MM/DD/YYYY) 
/            /  
Number of Capsules Given 
 
Number of Capsules Returned 
 
Discrepancy (Circle) 
Yes            No 
Site Staff Initials