Phase I Study of Irinotecan Liposome (Nal-IRI), Fluorouracil and Rucaparib in the Treatment of Select Gastrointestinal Metastatic Malignancies Followed by a Phase Ib of First and Second Line Treatment of Both Unselected and Selected (for BRCA 1/2 and PALB2 Mutations) Patients With Metastatic Adenocarcinoma of the Pancreas Then Followed by a Phase II Study of First Line Treatment of Selected Patients With Metastatic Adenocarcinoma of the Pancreas With Genomic Markers (Signature) of Homologous Recombination Deficiency (HRD)
Phase: PHASE1
Conditions: Metastatic Biliary Tract Carcinoma, Metastatic Colorectal Carcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma, Metastatic Malignant Digestive System Neoplasm, Metastatic Pancreatic Adenocarcinoma, Stage IV Colorectal Cancer AJCC v7, Stage IV Pancreatic Cancer AJCC v6 and v7, Stage IVA Colorectal Cancer AJCC v7, Stage IVB Colorectal Cancer AJCC v7
Sponsor: Academic and Community Cancer Research United

 
 
ACCRU-GI-1603 
Academic and Community Cancer Research United (ACCRU) 
 
Phase I Study of Irinotecan Liposome (nal-IRI), Fluorouracil and Rucaparib in the Treatment of Select 
Gastrointestinal Metastatic Malignancies Followed by a Phase Ib of First and Second Line Treatment of  
both Unselected and Selected ( for BRCA 1/2 and PALB2 Mutations) Patients with Metastatic 
Adenocarcinoma of the Pancreas then Followed by a Phase II Study of First Line Treatment of Selected 
Patients with Metastatic Adenocarcinoma of the Pancreas with Genomic Markers (Signature) of 
Homologous Recombination Deficiency (HRD) 
 
For any communications regarding this protocol, please 
contact the person listed on the Protocol Resource page.  
This is a stand-alone document found on the ACCRU web site (
).  
 
 
Study Chairs 
 
 
 
ACCRU: 
 
 
 
  
 
 
 
Statistician: 
 
 
  
 
√ Study contributor(s) not responsible for patient care. 
 
 
Drug Availability  
Commercial Agents:  Fluorouracil (5-FU), Leucovorin 
Drug Company Supplied:  Rucaparib and nal-IRI (IND Exempt) 
 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
 
Document History 
Effective Date 
Pre-activation ACCRU 
September 8, 2017 
Activation ACCRU 
Amendment 2 
Amendment 3 
Amendment 4 
June 22, 2018 
August 28, 2019 
February 17, 2020 
November 19, 2021 
 

 
2  
ACCRU-GI-1603 
 
 
Addendum 4 
 
Index 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping Factor 
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 
Appendix IA - Consent Form – Phase I 
Appendix IB – Consent Form – Phase Ib 
Appendix II – Patient Medication Diary 

 
 
ACCRU-GI-1603 
Schema - Phase I (Limited Sites) 
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration Office (
 for dose level and to ensure that a place on the protocol is open for the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Cycle = 28 days 
 
 
 
 
 
 
Registration 
Patients with the following types of metastatic cancers will be included: 
1) Pancreatic (up to 2 lines of prior systemic therapies for metastatic disease),  
2) Colorectal (up to 3 lines of prior systemic therapies for metastatic disease),  
3) Gastroesophageal (up to 1 line of prior systemic therapy for metastatic 
disease), and  
4) Biliary Tract (up to 1 line of prior systemic therapy for metastatic disease)  
 
Nanoliposomal Irinotecan (nal-IRI) 
+ 
Fluorouracil (5-FU) 
+ 
Leucovorin 
+ 
Rucaparib 
(at assigned dose and corresponding 
days of each cycle*) 
Progression, refusal, unacceptable 
toxicity, alternative therapy  
at any time 
Event Monitoring 
(3 years) 

 
4  
ACCRU-GI-1603 
 
 
Addendum 4 
 
Schema – Phase Ib (Limited Sites) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle = 28 days 
 
   
 
 
 
 
 
Registration 
 
Patients with the following types of cancer will be included: 
 
1) Unknown/Non-HRD cohort: Metastatic pancreatic cancer (< 1 line of prior therapy 
in the metastatic setting) with unknown mutation status or wildtype for all of the 
following genes: BRCA1, BRCA2, PALB2. 
and   
 2) Known HRD cohort: Metastatic pancreatic cancer (< 1 line of prior therapy in the 
metastatic setting) with known mutation in any of the following genes: BRCA1, 
BRCA2, PALB2  (< 1 line of prior therapy in the metastatic setting) 
Nanoliposomal Irinotecan (nal-
IRI) 
(at recommended dose level 
determined during the Phase I 
portion of this study) 
+ 
Fluorouracil (5-FU) 
 
+ 
 
Rucaparib 
(at recommended dose level 
determined during the Phase I 
portion of this study) 
Progression, refusal, 
unacceptable toxicity, 
alternative therapy at any time 
Event Monitoring 
(3 years) 

 
5  
ACCRU-GI-1603 
 
 
Addendum 4 
 
Schema - Phase II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Dose of nal-IRI and rucaparib will be the recommended dose determined in the Phase I portion of this 
study. 
 
Cycle = 28 days 
 
 
Generic name: Nanoliposomal Irinotecan (nal-IRI) 
Brand name(s): Onivyde 
Availability:    Clinical Research Services, 
A division of Rx Crossroads by McKesson 
 
Generic name:  Rucaparib 
 
Brand name(s):  Rubraca® 
Availability:    Clinical Research Services, 
A division of Rx Crossroads by McKesson 
 
Generic name: 5 Fluorouracil (5-FU) 
Brand name(s):  Aldrucil®, Efudex®   
Availability:   Commercial Supply  
Generic name:  Leucovorin 
Availability:   Commercial Supply  
Registration 
(Patients with metastatic adenocarcinoma 
of the pancreas with genomic markers 
(signature) of homologous recombination 
deficiency (HRD) will be included) 
Nanoliposomal Irinotecan (nal-
IRI) * 
+ 
Fluorouracil (5-FU) 
+ 
Rucaparib * 
Progression, refusal, 
unacceptable toxicity, 
alternative therapy 
 at any time 
Event Monitoring 
(3 years) 
Pre-Registration for HRD 
screening 

 
6  
ACCRU-GI-1603 
 
 
Addendum 4 
 
 
 
1.0 
Background   
 
1.1 
Pancreatic Cancer: 
 
Pancreatic cancer remains the most lethal cancer with less than 6% five-year overall 
survival across all stages and despite recent advances with the advent of gemcitabine and 
nab-paclitaxel or FOLFIRINOX.1-3 It is the 4th most deadly cancer in the Western world 
and is poised to become the second most deadly by 2030.4 There is an urgent need to 
improve selection of patients for current and emerging therapeutic strategies. 
 
1.2 
Genomic Instability in Pancreatic Cancer: 
 
Pancreatic cancer is characterized by genomic instability, and several genetic mutations 
have been described causing DNA repair defects, such as those involving the DNA 
mismatch repair gene MLH1 (3-15% incidence), the tumor suppressor genes p53 (50% 
incidence), BRCA1/2 and PALB2 (7% incidence in sporadic and up to 17% in familial 
cases), and the Fanconi anemia genes FANCC and FANCG (5-10%).5 Other key factors 
in DNA repair including ATM/Chk2, ATR/ Chk1, Rad51, ERCC1, and PTEN, can be 
mutated or inactivated in pancreatic cancer.6 Impaired DNA damage response pathways 
in pancreatic cancer may create vulnerabilities in cancer cells that can be exploited 
therapeutically. 
 
Recent genomic analysis of pancreatic cancer has revealed a complex mutational 
landscape, with whole genomic analysis redefining the mutational landscape of 
pancreatic cancer. A recent study defined genomic markers of defective DNA 
maintenance as well as defective DNA repair genes without BRCA pathway mutation.7 
Taking into account mutations of the BRCA pathway components, both somatic and 
germline, as well as putative surrogate measures of deficiencies in DNA maintenance 
(unstable genome and the BRCA mutational signature), germline mutations in BRCA (1 
and2) count for only 4% of all patients. Overall, mutations in the BRCA pathway 
component genes and surrogate measures of defect in DNA maintenance have potential 
implications in selection for pancreatic cancer. As such it is likely these genomic 
biomarkers of defective DNA maintenance (BRCAness) will also benefit from therapies 
targeting DNA damage response.8  
 
1.3 
PARP inhibitors: 
 
Poly-(ADP-ribose) polymerase 1 and 2 (PARP1 and 2) are nuclear enzymes activated by 
DNA single-strand breaks resulting from exposure to DNA damaging agents, which 
facilitate DNA repair via BER. PARP is essential in recognition and repair of DNA 
damage.9 Interim results from an ongoing phase II trial with single agent olaparib in 
germline BRCAm-associated advanced solid tumors yielded close to 60% CBR (22% 
ORR).10 Veliparib was tested in a phase 2 study in patients with advanced ovarian cancer 
with germline BRCA mutations. The response rate was 26%. The median PFS was 8 
months.11  
 
RUCAPANC is a  study of rucaparib using 600 mg PO bid in refractory pancreatic 
cancer with BRCA mutations (somatic or germline).12 In the first 19 patients on study 
(median = 2 prior lines of therapy), rucaparib as a single agent has shown evidence of 

 
7  
ACCRU-GI-1603 
 
 
Addendum 4 
 
significant and sustainable impressive single agent activity (Figure 1). Interestingly, 
objective responses were only observed after cycle 2 (Figure 1)  
Figure 1:  
 
 
In the TOPARP-A study, 50 patients with advanced prostate cancer refractory to standard 
of care were treated with olaparib. 16 (33%) had genetic aberrations in the DNA repair 
pathway.  14 out of 16 (88%) had a partial response to olaparib.28 
 
1.4 
Nanoliposomal Irinotecan in Pancreatic Cancer: 
 
Nanoliposomal irinotecan (nal-IRI) comprises irinotecan free-base encapsulated in 
liposome nanoparticles.13 The liposome is designed to keep irinotecan in the circulation 
sheltered from SN-38 conversion longer than free (unencapsulated) irinotecan. This will 
increase and prolong intratumoral levels of both irinotecan and SN-38 compared with 
free irinotecan. This amounts to ~ 6 fold higher level of SN-38 found in tumors compared 
to plasma at 72 hours which suggests local metabolic activation of irinotecan.  
 
Clinically, the combination of nal-IRI plus fluorouracil (5-FU)/leucovorin (LV) conferred 
a significant improvement in outcome over 5-FU/LV response rate of 16% (vs. 1%) and 
overall survival rate of 6.1 months (vs. 4.2 mos) in patients with metastatic PDAC who 
have progressed to first line that included gemcitabine.14 It is now considered a standard 
and approved second line regimen in metastatic pancreatic adenocarcinoma. Studies to 
establish a role for the combination in first line are underway.  
 
1.5 
Synergistic Cytotoxicity with Irinotecan, NKTR-102, nal-IRI and SN-38: 
 
Irinotecan and rucaparib have been demonstrated to display synergistic anti-tumor effects 
in vitro and in vivo. DNA damaging agents are the cornerstone treatment for pancreatic 

8  
ACCRU-GI-1603 
Addendum 4
cancer and blocking DNA repair may prevent chemo-resistance. 
Topoisomerase inhibitors have been shown to induce PARP cleavage. Moreover, PARPi 
have been shown to enhance cytotoxicity of topoisomerase inhibitors such as nal-IRI and 
irinotecan.15 For example, the DNA damage induced by irinotecan requires PARP-1 for 
efficient repair, and co-treatment with PARPi results in persistent and increased DNA 
damage breaks and apoptosis compared to irinotecan alone. These mechanisms explain 
the synergistic cytotoxicity observed between topoisomerase and PARP inhibitors in 
preclinical models. 
Table 1: Combination of rucaparib and SN-38 is synergistic in multiple pancreatic cell line models 
in vitro*
*Synergistic combination in naïve cell lines typically insensitive to rucaparib alone
*Stronger synergy observed in models where HR deficiency is induced (siBRCA1/2, siPALB2, 
siRAD51C)
The combination of rucaparib and SN-38 was found to be synergistic in multiple 
pancreatic cell line models in vitro with increased sensitivity to rucaparib or SN-38 when 
BRCA< ATR, RAD51C or PALB2 is knocked down (Table 1). Rucaparib and irinotecan 
have been demonstrated to exhibit synergistic antitumor effects. Additionally, rucaparib 
combined with etirinotecan pegol (NKTR-102) with a range of low- to high-doses for 
both agents showed similar evidence of synergism in MX-1 breast cancer model with 
complete responses and no re-growth at all levels. 
1.6 
Optimizing Dosing Strategies 
BLISS analyses of rucaparib + SN-38 in PANC-1 (WT BRCA) or in BRCA1 deficient 
PANC1 (siRNA) suggest that maximal impact is observed when half of the efficacious 
does for each agent is combined. Adding a low dose of rucaparib to half maximal dose of 
SN-38 has a large effect whereas adding SN-38 to half maximal rucaparib dose has a 
gradual effect on cell viability. Combining the long-acting topoisomerase 1-inhibitor 
etirinotecan pegol with the PARP inhibitor rucaparib resulted in synergy and durable 
complete responses in a BRCA1-deficient MX-1 breast cancer model.16
One strategy aiming to optimize dose schedule is sequential dosing to maximize 
therapeutic index for the nal-IRI/PARPi combination. Delaying dosing of PARPi is 
predicted to allow maximizing exposure in tumor, while minimizing systemic toxicity. 
Delaying exposure of PARPi by 48-72 hours following nal-IRI administration may allow 
minimizing toxicity while achieving a higher MTD for the PARPi. Preclinical proof of 

 
9  
ACCRU-GI-1603 
 
 
Addendum 4 
 
concept studies suggest that, at lower doses of nal-IRIa 48-hour delay may be optimal, 
while at higher doses, a 72-hour delay may be necessary. 
 
1.7 
Experience with other PARPi 
 
Talazoparib (BMN 673), another highly potent and specific PARPi, has demonstrated 
synergy with irinotecan including synergy in BRCA1 mutant MX-1 model.17  
Etirinotecan pegol (NKTR-102, pegylated irinotecan) is designed to provide extended 
drug exposure to the tumor and in preclinical models showed improved efficacy and 
tolerability over irinotecan. Recently, preclinical data indicate that the combination of 
NKTR-102 and talazoparib is better tolerated than that of irinotecan and talazoparib, and 
results in stronger combination anti-tumor activity. 
 
Clinically, FOLFIRI in combination with veliparib in a Phase I trial included 13 patients 
with refractory pancreatic cancer irrespective of BRCA1/2 status. Response and stable 
disease rates were 15% and 46% respectively with 6-month time-to-progression was 
27%. Both responses were long lasting and occurred in non-BRCA mutated patients.  
Additionally, talazoparib and olaparib were both found to be safe to combine with 
irinotecan with preliminary meaningful activity noted with the respective combinations.  
 
1.8 
Homologous Recombination Deficiency (HRD) Signature  
 
Current HRD biomarker for pancreatic includes BRCA1/2 and PALB2 (Germline and 
Somatic). The FoundationOne test utilizes next-generation sequencing to identify 
alterations in all somatic genes in human solid tumor cancers. FoundationOne 
interrogates the entire coding sequence of 315 cancer-related genes plus select introns 
from 28 genes often rearranged or altered in solid tumor cancers. These genes are known 
to be somatically altered in solid cancers based on recent scientific and clinical literature 
and are sequenced at great depth to identify the relevant, actionable somatic alterations, 
including single base pair change, insertions, deletions, copy number alterations, and 
selected fusions.” 
  
Foundation Medicine is also developing a plasma-based test that measures circulating 
free DNA (cfDNA), which will include the HRD signature for pancreatic and other target 
solid tumors. This will be available very soon and will be a key component of this study 
(and likely the future of genomic testing. cfDNA offers multiple advantages over tissue 
based testing.  First, the difficulty of getting adequate tumor biopsies from most GI 
cancers makes this type of test more attractive for screening patients. It also represents a 
“real-time” snapshot of the genomic heterogeneity of the residing cancer.  Additionally, 
analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted 
therapies. cfDNA profiles allow the detection of concomitant resistance mechanisms 
residing in separate metastases and assessment of the effect of therapies designed to 
overcome resistance. Recent work has shown that patients with HRD are more likely to 
respond to PARP inhibitors. Indeed, a phase 2 trial (ARIEL trial) in patients with 
advanced ovarian cancer with HRD or genome-wide loss of heterozygosity (LOH) 
showed increased response rate compared to wild-type patients (RR 66%, 32% and 11% 
for patients with HRD vs. LOH vs. wild-type).18 
 
Information on the FoundationOne test can be found at the following website 
 
 

 
10  
ACCRU-GI-1603 
 
 
Addendum 4 
 
 
 
1.9 
Rationale 
 
Pancreatic cancer remains the most lethal cancer despite recent advances. It is the 4th 
most deadly cancer in the Western world and is poised to become the second most deadly 
by 2030.4 There is an urgent need to improve selection of patients for current and 
emerging therapeutic strategies.  
 
Impaired DNA damage response pathways known as homologous recombination 
deficiency (HRD), in pancreatic cancer, may create vulnerabilities in cancer cells that can 
be exploited therapeutically.19 Surrogate measures of defects in DNA maintenance along 
with mutations in the BRCA pathway account for about 25% of all pancreatic cancer 
patients. These tumors are expected to exhibit sensitivity to DNA-damaging agents. 
 
PARP is essential in recognition and repair of DNA damage. Preliminary data suggests 
significant promise for inhibitors of PARP with rucaparib showing single agent durable 
responses in refractory pancreatic cancer patients with BRCA mutations (somatic or 
germline). Nanoliposomal irinotecan (nal-IRI) comprises irinotecan free-base 
encapsulated in liposome nanoparticles. The combination of nal-IRI plus 5-FU/LV is now 
considered a standard and approved post-gemcitabine exposure regimen in pancreatic 
adenocarcinoma with studies underway to establish a role for the combination as a first-
line regimen is underway.  There is significant evidence of the synergistic cytotoxicity 
observed between topoisomerase and PARP inhibitors in preclinical models. Rucaparib 
and irinotecan have been demonstrated to exhibit synergistic antitumor effects and there 
may be preliminary evidence of a larger synergism with novel delivery formulations of 
irinotecan.  
 
Strategies aiming to optimize dose schedule include sequential dosing to maximize 
therapeutic index for the nal-IRI/PARPi combination. Delaying dosing of PARPi is 
predicted to allow maximizing exposure in tumor, while minimizing systemic toxicity 
with preclinical proof of concept studies suggest that at lower doses of nal-IRI, a 48-hour 
delay may be optimal while at higher doses a 72-hour delay may be necessary. As such 
our initial dosing strategy includes staggered approach schedule with nal-IRI 
administered on day 1, with rucaparib administered on days 4-13 of every 14-day half 
cycle. G iven all of the above, we hypothesize that the combination of nal-IRI (nal-IRI) 
and 5-FU combined with rucaparib will improve outcome in patients with untreated 
metastatic pancreatic cancer with genomic markers (signature) of homologous 
recombination deficiency (HRD). The phase I portion of this study is designed to 
determine the maximum tolerated dose of nal-IRI/5-FU/LV +rucaparib in patients with 
select GI malignancies that have known sensitivities to irinotecan and would likely 
benefit from the addition of the PARP inhibitor (pancreatic, colorectal, gastroesophageal, 
and biliary tract cancer).20-22 This is followed by an exploratory expansion cohort (Phase 
Ib study) of patients with metastatic pancreatic both unselected and selected for BRCA 
1/2  and PALB2 mutations . The phase II pancreatic cancer study will select for an HRD 
signature (based on cfDNA) that encompasses BRCA 1/2, PALB2 mutations, BRCA-like 
alterations and defects independent of BRCA mutations under development by Clovis 
and Foundation Medicine. This HRD signature will likely identify patients most likely to 
respond to rucaparib. 
  
The phase I portion of this study is designed to determine the maximum tolerated dose 

 
11  
ACCRU-GI-1603 
 
 
Addendum 4 
 
(MTD) and administrative schedule of nal-IRI + rucaparib combination in patients with 
select GI malignancies (pancreas, colorectal, gastroesophageal, and biliary tract cancer).  
 
The expansion cohort (Phase Ib) of patients with metastatic disease from pancreatic 
cancer will be accrued for exploratory analysis.  
 
The MTD and administrative schedule determined in the phase I portion of the trial will 
be used as the starting dose for Phase II. The phase II portion will use a 2-stage Simon 
design to assess the proportion of evaluable patients who reach CR/PR ≤32 weeks, and an 
interim analysis with relaxed probability of stopping for futility to assess the efficacy of 
nal-IRI+ rucaparib in patients with untreated pancreatic cancer with BRCA1/2 and 
PALB2. Patients with untreated pancreatic cancer with HRD other than BRCA1/2 and 
PALB2 will be accrued for exploratory analysis.  
 
2.0 
Goals    
 
2.1 
Phase I Portion 
 
 
 
2.11 
Primary Aim: To establish the recommended dose level for the Phase Ib and 
Phase II trial of nal-IRI and 5-FU with rucaparib (MFR) in patients with 
metastatic disease from pancreatic cancer (up to 2 lines of prior therapy), 
colorectal cancer (up to 3 lines of prior therapy), gastroesophageal cancer (up to 
1 line of prior therapy) and biliary tract cancer (with 1 line of prior therapy 
allowed). 
 
2.2 
Phase Ib Portion 
 
2.21 
Primary Aim: To assess, in a preliminary fashion, antitumor efficacy, in terms of 
Disease Control Rate and further tolerability of the recommended dose level of 
combination of nal-IRI and 5-FU with rucaparib in patients with metastatic 
disease from pancreatic cancer (< 1 line of prior therapy in the metastatic 
setting).  
 
2.3 
Phase II Portion 
 
2.31 
Primary Aim: To estimate the proportion of evaluable patients who reach CR/PR 
≤32 weeks after registration among patients with metastatic adenocarcinoma of 
the pancreas with genomic markers (signature) of homologous recombination 
deficiency (HRD), specifically BRCA1, BRCA2, and PALB2 mutation, treated 
with the combination of nal-IRI and 5FU with rucaparib (MFR).   
 
2.32 
Secondary Aims: 
 
 
1) To estimate the progression-free survival (PFS) and overall survival (OS) for 
patients with metastatic adenocarcinoma of the pancreas with genomic markers 
(signature) of homologous recombination deficiency (HRD), specifically 
BRCA1, BRCA2, and PALB2 mutation, treated with the combination of nal-IRI 
and 5-FU with rucaparib (MFR). 
 
 
2) To assess the toxicity of the combination of nal-IRI and 5-FU with rucaparib 
in patients with metastatic adenocarcinoma of the pancreas with  
 
genomic markers (signature) of homologous recombination deficiency (HRD), 
specifically BRCA1/2 and PALB2 mutations. 

 
12  
ACCRU-GI-1603 
 
 
Addendum 4 
 
 
2.4 
Exploratory Objectives 
 
2.41 
To evaluate the role of genomic markers (signature) of HRD, mutation other than 
BRCA1, BRCA2, and PALB2 as predictive biomarkers of response to MFR. 
 
2.42 
To evaluate BRCA1, BRCA2, and PALB2 mutations as predictive biomarker of 
response to MFR. 
 
3.0 
Patient Eligibility  
 
Phase I: Prior to discussing protocol entry with the patient, call the ACCRU Registration 
Office 
 for dose level and to ensure that a place on the protocol is open to the 
patient.  
 
 
*No waivers on eligibility per ACCRU 
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥18 years. 
 
3.12 
Phase I only: Histologic confirmation of pancreatic, colorectal, gastroesophageal 
or biliary adenocarcinoma, as follows: 
• 
Patients with metastatic disease from pancreatic cancer who received no 
more than 2 lines of prior therapy in the metastatic setting. 
• 
Patients with metastatic disease from colorectal cancer who received no 
more than 3 lines of prior therapy in the metastatic setting. 
• 
Patients with metastatic disease from gastroesophageal cancer who 
received no more than 1 line of prior therapy in the metastatic setting. 
• 
Patients with metastatic disease from biliary tract cancer who received no 
more than 1 line of prior therapy in the metastatic setting. 
    
NOTE: No prior exposure to irinotecan in the metastatic setting will be allowed 
except in the phase I dose escalation portion and in colon cancer patients only. In 
pancreas cancer, exposure to irinotecan is only allowed in the neoadjuvant setting 
and no progressive disease <3 months from last dose of irinotecan.  
 
3.13 
Phase Ib only: Patients with metastatic adenocarcinoma of the pancreas who 
have received no more than 1 line of prior therapy in the metastatic setting. 
 
NOTE: Exposure to irinotecan is only allowed in the neoadjuvant setting and no 
progressive disease <3 months from last dose of irinotecan. 
 
 
3.14 
Phase II only: Patients with metastatic adenocarcinoma of the pancreas with 
genomic markers (signature) of homologous recombination deficiency (HRD) or 
BRCA1 or BRCA2 or PALB2 mutation, or HRD (non-BRCA, non-PALB) who 
have not received any systemic therapy in the metastatic setting.  
 
NOTE: Exposure to irinotecan is only allowed in the neoadjuvant setting and no 
progressive disease <3 months from last dose of irinotecan. 

 
13  
ACCRU-GI-1603 
 
 
Addendum 4 
 
 
3.15 
Measurable disease as defined in Section 11.0.    
 
3.16 
ECOG Performance Status (PS) 0 or 1 (form is available on the ACCRU web 
site).  
 
3.17 
The following laboratory values obtained ≤21 days prior to registration.  
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin >9.0 g/dL 
• 
Total bilirubin ≤ institutional upper limit of normal (ULN)   
• 
Aspartate transaminase (AST) ≤3 x ULN, ≤ 5.0 x ULN for patients with 
metastatic disease to the liver 
• 
Aminotransferase (ALT) ≤3.0 x ULN, ≤ 5.0 x ULN for patients with 
metastatic disease to the liver 
• 
Creatinine ≤1.0 mg/dL or creatinine clearance ≥45 ml/min using the 
Cockcroft-Gault formula below: 
 
 
3.18 
Negative serum or urine pregnancy test done ≤7 days prior to registration and 
repeated prior to dosing on day 1 of each cycle, for individuals of childbearing 
potential only. 
 
 
NOTE: Individuals are considered to be of childbearing potential unless one of 
the following applies: 
 
• Is postmenopausal, defined as no menses for at least 12 months without 
an alternative medical cause. A high follicle-stimulating hormone (FSH) 
level consistently in the postmenopausal range (30 mIU/mL or higher) 
may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy; however, in 
the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient to confirm a postmenopausal state: or   
 
• Considered to be permanently sterile. Permanent sterilization includes 
hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy. 
 
3.19a 
Provide informed written consent. 
 
3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
Note:  During the Active Monitoring Phase of a study (i.e., active treatment and 
observation), participants must be willing to return to the consenting institution 
for follow-up. 
 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg) 
  
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 

 
14  
ACCRU-GI-1603 
 
 
Addendum 4 
 
3.19c 
Willing to provide tissue and blood samples for mandatory correlative research 
purposes (see Sections 6.0, 14.0 and 17.0).  
 
3.19d Individuals of reproductive potential and their partners willing to practice total 
abstinence or use a highly effective method of contraception (failure rate < 1% 
per year) during treatment and for 6 months following the last dose of rucaparib. 
 
The following are allowable only: 
• Ongoing use of progesterone-only injectable or implantable 
contraceptives (eg, Depo Provera, Implanon, Nexplanon) 
• Placement of an intrauterine device or intrauterine system 
• Bilateral tubal occlusion 
•  Sterilization, with appropriate post-vasectomy documentation of absence 
of sperm in ejaculate 
• True, complete (as opposed to periodic) abstinence. 
 
 
3.19e 
Patients must discontinue prior chemotherapy ≥ 28 days before registration.  
 
3.2 
Exclusion Criteria 
 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant individuals 
• 
Nursing individuals 
• 
Persons of childbearing potential who are unwilling to employ adequate 
contraception  
 
3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.23 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.   
 
3.24 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.25 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
 
3.26 
Previous or concurrent cancer that is distinct in primary site or histology from 
cancer of primary site ≤3 years prior to registration EXCEPT for curatively 
treated cervical cancer in situ, melanoma in situ, non-melanoma skin cancer and 
superficial bladder tumors [Ta (Non-invasive tumor), Tis (Carcinoma in situ) and 
T1 (Tumor invades lamina propria)]. Note: All cancer treatments for those 
distinct in a primary site other than cancer of origin must be completed ≥3 years 
prior to registration.  

 
15  
ACCRU-GI-1603 
 
 
Addendum 4 
 
 
 
 
3.27 
Received any prior PARPi treatment.  Patients who received prior PARPi 
treatment in the adjuvant setting with the last dose received more than 12 months 
prior to registration are allowed to enroll. 
 
3.28  
QTc prolongation > 480 msec, as calculated by either the Bazett or Fridericia 
formula, as per institutional standard. 
 
3.29 
Inability to swallow.

 
16 
ACCRU-GI-1603 
4.0 
Test Schedule 
 
NOTE: Variation of ≤4 days of scheduled visit is permitted. 
 
 
 
Tests and procedures 
 
≤21days 
prior to 
registration  
 
≤7days 
prior to 
registration 
Active Monitoring 
 
Prior to 
dosing on 
Day 1 of 
each 
cycle,* 
Beginning 
with 
Cycle 1 
(until PD) 
 
Day 15 of 
each cycle, 
Beginning 
with Cycle 1 
(until PD) 
 
Prior to 3rd 
and 
subsequent 
odd cycles 
(until PD) 
 
End of 
Treatment 
( PD, 
withdrawal, 
or removal) 
Observation8: 
30 days of End 
of Treatment 
History and exam, wt, ECOG PS 
X 
 
X 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
Adverse event assessment 
X 
 
X 
X 
 
X 
X7 
Hematology: 
CBC/ differential  
Chemistry:  SGOT (AST), SGBT 
(ALT), alk phos, T. bili, creatinine, 
calcium, phos, glucose, Na, K 
X 
 
X 
X 
 
X 
X 
Tumor measurement1 
X 
 
 
 
X 
X 
 
Pregnancy test2 
 
X 
X 
 
 
 
 
Mandatory archival tissue 
collection 5, R (See Section 17) 
X 
 
 
 
 
 
 
cfDNA4, R 
 
 
X 
 
X 
X 
 
ECG6 
X 
 
X 
 
 
 
 
Cancer markers: CEA (colorectal 
cancer) and CA19-9 
(cholangiocarcinoma) 4 R 
X 
 
 
 
X 
X 
 
Patient Medication Diary3 
 
 
X 
 
 
X 
 
*   Cycle = 28 days. 
 
(Footnotes on next page) 

 
17  
ACCRU-GI-1603 
 
1. Imaging should be done using CT scan (MRI if CT is not feasible). Use same imaging throughout the study. If patient is on study for more 
than 2 years, allow scans 3-4 months apart. 
 
2. For individuals of childbearing potential only.  Negative urine or serum pregnancy test must be done ≤7 days prior to registration and 
repeated prior to dosing on day 1 of each cycle. If a patient becomes pregnant during the study the investigator is to stop dosing with study 
drug(s) immediately. (See Section 10.314 for additional information.) 
 
3. The diary must begin the day the patient starts taking the medication 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. 
 
4. Mandatory blood draws (STRECK, EDTA and No Additive tubes) for research should not be collected and submitted until after the patient 
is registered onto the study, and should be done prior to dosing on Cycle 1, Day 1, then Day 1 of subsequent odd cycles, and end of 
treatment. Kits are required for this collection (See Section 14.0). 
 
5. Receipt of archival tumor tissue is not required for study registration and initiation of therapy. However, it is mandatory to receive the 
required tissue within 60 days from registration.   
 
6. Dose-escalation phase I, ECG should be done on baseline and Cycle 2, Day 1, measured twice at least 5 minutes apart. For Phase Ib and II 
– ECG should be done prior to cycle 1 only, then as indicated. 
 
7. Any Adverse event assessment within 30 days of end of treatment will be recorded on the adverse event assessment form in the last cycle 
of treatment. 
 
8. Treatment decision/patient care for patients who are off protocol treatment is at the discretion of the treating physician.  The observation 
period is recommended by the study protocol but no data collection is required other than adverse event assessment (See Footnote 7) 
 
R Research funded (see Section 19.0) 
 
 
Event Monitoring: Patients will be followed for survival every 6 months for 3 years from registration. This can be done via a phone call to the 
patient and does not require the patient to return to the consenting site. 

 
18  
ACCRU-GI-1603 
 
 
5.0 
Grouping Factors:  
 
• 
Phase I (Dose Escalation)- pancreatic vs.  
• 
Phase I (Dose Escalation)- colorectal vs.  
• 
Phase I (Dose Escalation)- gastroesophageal vs.  
• 
Phase I (Dose Escalation)- biliary tract vs.  
• 
Phase Ib (Dose Expansion)-pancreatic, Unknown/non-HRD patients vs.  
• 
Phase Ib (Dose Expansion)-pancreatic, HRD patients vs. 
• 
Phase II. 
 
6.0  
Registration/Randomization Procedures 
 
6.1 
Phase I 
 
Prior to discussing protocol entry with the patient, call the ACCRU Registration 
Office (507-284-4130) for dose level and to ensure that a place on the protocol is 
open to the patient.  
 
6.11 
Registration Procedures 
 
6.111 To register a patient, fax 
a completed eligibility checklist 
to the Academic and Community Cancer Research United (ACCRU) 
Registration Office between 8 a.m. and 4:30 p.m. central time Monday 
through Friday.   
 
6.112 Documentation of IRB approval must be on file with ACCRU before an 
investigator may register any patients. Approvals should be uploaded 
through the online ACCRU Regulatory Management System (ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB 
approval documentation must be on file with ACCRU no less than 
annually.  Approvals should be uploaded through the online ACCRU 
Regulatory Management System (ARMS). If the necessary 
documentation is not submitted in advance of attempting patient 
registration, the registration will not be accepted and the patient may not 
be enrolled in the protocol until the situation is resolved. 
 
Submission of annual IRB approvals to ACCRU is required until the 
study is closed through your IRB. 
 
6.113 Prior to accepting the registration, registration/randomization application 
will verify the following: 
• IRB approval at the registering institution 
• Patient eligibility 
• Existence of a signed consent form 
• Existence of a signed authorization for use and disclosure of 
protected health information  
 
 
 

 
19  
ACCRU-GI-1603 
 
 
6.2 
Phase Ib 
 
6.21 
Registration Procedures 
 
To register a patient, access the ACCRU web page at 
go to the 
Application section and click on “Registration” and enter the 
registration/randomization application. The registration/randomization 
application is available 24 hours a day, 7 days a week. Back up and/or system 
support contact information is available on the Web site. If unable to access the 
Web site, call the Academic and Community Cancer Research United (ACCRU) 
Registration Office at 
between the hours of 8 a.m. and 4:30 p.m. 
Central Time (Monday through Friday). 
 
Instructions for the registration/randomization application are available on the 
above web page under the Study Resources section, “Application Training.” 
 
Prior to initiation of protocol study intervention, this process must be completed 
in its entirety and a ACCRU subject ID number must be available as noted in the 
instructions. It is the responsibility of the individual and institution registering the 
patient to confirm the process has been successfully completed prior to release of 
the study agent. Patient registration via the registration/randomization application 
can be confirmed in any of the following ways: 
 
· Contact the ACCRU Registration Office 
If the patient was 
fully registered, the Registration Office staff can access the information from the 
centralized database and confirm the registration. 
 
· Refer to “Application Training” at 
click on “Registration, 
Installation & Entry Instructions”. 
 
6.3 
Phase II 
 
6.31 
Pre-Registration (Step 0) 
 
6.311 To pre-register a patient, access the ACCRU web page at 
 
go to the Application section, click on “Registration” and enter the 
registration/randomization application.  The registration/randomization 
application is available 24 hours a day, 7 days a week.  Back up and/or 
system support contact information is available on the Web site.  If unable to 
access the Web site, call the Academic and Community Cancer Research 
United (ACCRU) Registration Office at 
between the hours 
of 8 a.m. and 4:30 p.m. Central Time (Monday through Friday). 
 
Users should refer to the section titled “Pre-Registration Components” 
for details on how to pre-register a patient to a study.  At the time of pre-
registration the patient will receive an ACCRU patient identification 
number. This number is to be used when submitting tissue or blood 
samples, as applicable for the study (see Section 17.0).  Patient pre-
registration via the registration/randomization application can be 
confirmed in any of the following ways: 

 
20  
ACCRU-GI-1603 
 
 
 
• Contact the ACCRU Registration Office 
If the 
patient was pre-registered, the ACCRU Registration Office staff 
can access the information from the centralized database and 
confirm the registration. 
• Refer to “Application Training” at 
 
“Registration, Installation & Entry Instructions”. 
 
6.312 Documentation of IRB approval must be on file with ACCRU before an 
investigator may pre-register any patients. Approvals should be uploaded 
through the online ACCRU Regulatory Management System (ARMS). 
 
 
In addition to submitting initial IRB approval documents, ongoing IRB 
approval documentation must be on file with ACCRU no less than 
annually. Approvals should be uploaded online through ARMS. If the 
necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient 
may not be enrolled in the protocol until the situation is resolved. 
 
 
Submission of annual IRB approvals to ACCRU is required until the 
study has been permanently closed through your IRB.  
 
6.313 Prior to accepting the pre-registration, the registration/randomization 
application will verify the following: 
• IRB approval at the registering institution 
• Patient pre-registration eligibility 
• Existence of a signed consent form 
• Existence of a signed authorization for use and disclosure of 
protected health information  
 
6.32 
Registration (Step 1) 
 
Upon completion of the patient’s submitted blood or tissue evaluation status (see 
Sections 14.0 and/or 17.0), the person provided on the samples submission form 
will be contacted by fax with the results of the sample evaluations.  If based upon 
the sample evaluations the subject is approved for registration, the pre-registering 
institution must register the subject to the protocol.   
 
6.321 To register a patient, access the ACCRU web page at 
go 
to the Application section, click on “Registration” and enter the 
registration/randomization application.  The registration/randomization 
application is available 24 hours a day, 7 days a week.  Back up and/or 
system support contact information is available on the Web site.  If unable to 
access the Web site, call the Academic and Community Cancer Research 
United (ACCRU) Registration Office at 
between the hours 
of 8 a.m. and 4:30 p.m. Central Time (Monday through Friday). 
 
Users should refer to the section titled “Pre-Registration Component” for 
details on how to register a patient on step 2 of a study that has a pre-
registration and registration step.  The instructions for the 

 
21  
ACCRU-GI-1603 
 
 
registration/randomization application are available using the Help 
button.  Prior to initiation of protocol treatment, this process must be 
completed in its entirety and an ACCRU subject ID number must be 
available as noted in the instructions.  It is the responsibility of the 
individual registering the patient to confirm the process has been 
successfully completed prior to release of the study agent.  Patient  
registration via the registration/randomization application can be 
confirmed in any of the following ways: 
 
• Contact the ACCRU Registration Office 
 the 
patient was pre-registered, the ACCRU Registration Office staff 
can access the information from the centralized database and 
confirm the registration. 
• Refer to “Application Training” at 
 click on 
“Registration, Installation & Entry Instructions”. 
 
6.322 Documentation of IRB approval must be on file with ACCRU before an 
investigator may register any patients. Approvals should be uploaded 
through the online ACCRU Regulatory Management System (ARMS). 
 
In addition to submitting initial IRB approval documents, ongoing IRB 
approval documentation must be on file with ACCRU no less than 
annually.  Approvals should be uploaded through the online ACCRU 
Regulatory Management System (ARMS). If the necessary 
documentation is not submitted in advance of attempting patient 
registration, the registration will not be accepted and the patient may not 
be enrolled in the protocol until the situation is resolved. 
 
Submission of annual IRB approvals to ACCRU is required until the 
study is closed through your IRB. 
 
6.323 Prior to accepting the registration, registration/randomization application 
will verify the following: 
• IRB approval at the registering institution 
• Patient eligibility 
 
6.4 
Phase I/Ib and II 
 
6.41 
Correlative Research 
 
A mandatory correlative research component is part of this study, the patient 
will be automatically registered onto this component (see Sections 3.0, 14.0 and 
17.0). 
 
6.42 
At the time of registration, the following will be recorded: 
• Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn about, prevent, or treat cancer. 
• Patient has/has not given permission to store and use his/her blood sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example:  diabetes, Alzheimer’s disease, or heart disease). 

 
22  
ACCRU-GI-1603 
 
 
• Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn about, prevent, or treat cancer. 
• Patient has/has not given permission to store and use his/her tissue sample(s) 
for future research to learn, prevent, or treat other health problems (for 
example:  diabetes, Alzheimer’s disease, or heart disease). 
• Patient has/has not given permission for ACCRU to give his/her sample(s) to 
outside researchers. 
 
6.43 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a cancer specialist. 
 
 
6.44 
Treatment cannot begin prior to registration and must begin ≤21 days after 
registration. 
 
6.45 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.46 
All required baseline symptoms (see Section 10.52) must be documented and 
graded. 
 
6.47 
Study drug is available on site.  
 
6.48 
Blood draw kit is available on site.   
 
 

 
23  
ACCRU-GI-1603 
 
 
 
7.0 
 
Protocol Treatment 
 
 
7.1 
Treatment Schedule – Use actual weight with dose adjustments if weight changes more 
than 10% from baseline. 
 
 
 
Cycle = 28 days 
 
Agent 
Route 
Day 
Nanoliposomal 
Irinotecan (nal-IRI) 
IV 
Days 1 and 15 
Leucovorin (LV)* 
IV 
Days 1 and 15, 
prior to 5-FU 
Fluorouracil (5-FU) 
IV 
Days 1 and 15 
Rucaparib 
PO 
Twice each day on 
Days 4-13 and Days 
18-27 of a 28 day 
cycle. 
  
*If there is a shortage of leucovorin (LV) in the U.S., and you are unable to obtain 
access, LV may be held until supply is available. LV will not be administered in the 
phase Ib/II portion of the study  
 

 
24  
ACCRU-GI-1603 
 
 
7.11 
Planned Phase I Dose Escalation Levels: 
Dose 
Level 
Agent 
Dose 
Route 
Day 
DL-2 
Nanoliposomal 
irinotecan (nal-
IRI) 
43 mg/m2 
Intravenous  
over 90 minutes 
Days 1 and 15 
 
Leucovorin 
(LV) 
400 mg/m2 
Intravenous 
Days 1 and 15, prior to 
5-FU 
 
Fluorouracil 
(5-FU) 
2000 mg/m2 
Intravenous  
over 46 hours 
Days 1 and 15 
 
Rucaparib 
200 mg 
Oral 
Twice daily on Days 
4-13 and 18-27  
DL-1 
nal-IRI 
50 mg/m2 
Intravenous  
over 90 minutes 
Days 1 and 15 
LV 
400 mg/m2 
Intravenous 
Days 1 and 15, prior to 
5-FU 
5-FU 
2400 mg/m2 
Intravenous  
over 46 hours 
Days 1 and 15 
Rucaparib 
200 mg 
Oral 
Twice daily on Days 
4-13 and days 18-27 
DL1* 
nal-IRI 
50 mg/m2 
Intravenous  
over 90 minutes  
Days 1 and 15 
LV 
400 mg/m2 
Intravenous 
Days 1 and 15, prior to 
5-FU 
5-FU 
2400 mg/m2 
Intravenous  
over 46 hours  
Days 1 and 15  
Rucaparib 
 
400 mg 
Oral 
Twice daily on Days 
4-13 and days 18-27 
DL2-
A 
Nanoliposomal 
irinotecan (nal-
IRI) 
50 mg/m2 
Intravenous  
over 90 minutes 
Days 1 and 15 
Fluorouracil 
(5-FU) 
2400 mg/m2 
Intravenous  
over 46 hours 
Days 1 and 15 
Rucaparib 
600 mg 
Oral 
Twice daily on Days 
4-13 and days 18-27 
DL 2-
B 
nal-IRI 
70 mg/m2 
Intravenous  
over 90 minutes  
Days 1 and 15 
LV 
 
400 mg/m2 
Intravenous 
 
Days 1 and 15, prior to 
5-FU 
5-FU      
2400 mg/m2 
Intravenous  
over 46 hours 
Days 1 and 15 
Rucaparib 
 
400 mg 
Oral 
Twice daily on Days 
4-13 and days 18-27 
DL 3 
nal-IRI 
70 mg/m2 
Intravenous  
over 90 minutes  
Days 1 and 15 
Leucovorin 
400 mg/m2 
Intravenous  
 
Days 1 and 15, prior to 
5-FU 
5-FU 
2400 mg/m2 
Intravenous  
over 46 hours  
Days 1and 15 
Rucaparib 
600 mg 
Oral 
Twice each day on 

 
25  
ACCRU-GI-1603 
 
 
 
Days 4-13 and days 
18-27 
* Starting dose level  
Only patients with pancreatic, colorectal, gastroesophageal and biliary tract cancers will 
be included  
 
 
 
7.12   Phase Ib Dose Expansion (Phase Ib Study at recommended dose level determined 
by the Phase I portion): 
The recommended dose determined by phase I dose escalation is dose level 2-A 
(DL2-A in section 7.11) 
Agent 
Dose 
Route 
Day 
nal-IRI  
50 mg/m2 
(Recommended 
Dose 
Determined by 
Phase I Dose 
Escalation) 
Intravenous  
over 90 minutes 
Days 1 and 15 
5-FU 
2400 mg/m2 
Intravenous  
over 46 hours 
Day 1 and 15 
Rucaparib 
600 mg 
(Recommended 
Dose 
Determined by 
Phase I Dose 
Escalation) 
Oral 
Twice daily on Days 4-13 
and days 18-27 
(Recommended schedule 
determined by phase I dose 
escalation) 
 
7.13 
Phase II (Phase II study at recommended dose level determined by the Phase I 
portion) 
Agent 
Dose 
Route 
Day 
nal-IRI  
Recommended 
Dose 
Determined by 
Phase I Dose 
Escalation 
Intravenous  
over 90 minutes 
Days 1 and 15 
 
5-FU 
2400 mg/m2 
Intravenous 
over 46 hours 
Days 1 and 15 
Rucaparib 
Recommended 
Dose 
Determined by 
Phase I Dose 
Escalation 
Oral 
Twice daily on days as 
determined by Phase I 
administration schedule 
 
 
 

 
26  
ACCRU-GI-1603 
 
 
7.14 
Pretreatment medication   
 
Agent* 
Dose 
Route 
Day 
 
Dexamethasone 
 
10 mg 
 
 
IV  
Per institutional guidelines 
Ondansetron 
8mg  
IV 
Per institutional guidelines 
 
*Other pretreatment meds can be used per institutional guidelines. 
 
 
7.2 
For this protocol, the patient must return to the consenting ACCRU institution for 
evaluation at least every 14 days during treatment. 
 
 
7.3 
Treatment by a local medical doctor (LMD):  
 
Patients must receive study treatment per protocol at the consenting ACCRU institution. 
However, patients are allowed to receive supportive care for any adverse events, as 
needed, at a non-ACCRU institution. 
 
7.4 
Phase I/Ib – determination of recommended dose level and dose expansion 
 
7.41 
Dose Escalation 
 
 
 
7.411 This portion of the study will include patients with metastatic disease 
from pancreatic cancer (up to 2 lines of prior therapy), colorectal cancer 
(up to 3 lines of prior therapy), gastroesophageal cancer (up to 1 lines of 
prior therapy) and biliary tract cancer (BTC; up to 1 line of prior therapy 
allowed). 
 
 
 
7.412 There will be 4 dose levels with two de-escalations to dose level -2 if 
dose level 1 is deemed intolerable (See Table 1).  
 
 
 
7.413 Three patients will be evaluated at each dose level and assessed for dose 
limiting toxicity (DLT) during cycle 1 (4 weeks).  Standard 3+3 dose 
escalation scheme is utilized (See Section 16.22 for MTD 
determination).  Maximum tolerated dose (MTD) is the highest dose at 
which no more than 1 of 6 patients will develop a DLT.   
 
 
 
7.414 The recommended dose level for Phase 1b and Phase 2 study will be 
determined based on MTD and discussion between the study team and 
the sponsor. 
 
 
 
7.415 Dose expansion: Following determination of the recommended dose 
level from the phase I study, the study will proceed to a phase 1b study 
of patients with metastatic adenocarcinoma of the pancreas who have 
received no more than 1 line of prior therapy in the metastatic setting. 
See Schema for further details.   
 
 
 
7.416 We will collect plasma samples (for cfDNA) from patients prior to 
initiation of therapy, prior to 3rd and subsequent odd cycles, and at 
progression. Paraffin embedded tissue (PET) will be collected as well. 

 
27  
ACCRU-GI-1603 
 
 
HRD analysis will be performed as a translational component to help 
correlate with response (prior to therapy) and development of resistance 
(during and at end of therapy). PET will be used for validation. The test 
requires ~ 5x 10uM FFPE sections. 
 
7.417 Similar to other follow up studies to NAPOLI, UGT1A1 will not be 
routinely required or tested. Testing will be performed on individual 
patients who may experience significant and unexpected toxicities are 
encountered. 
 
 
 
 
7.418 Investigators are to contact the ACCRU Operations Office via email at 
 as soon as any dose-limiting toxicity (DLT) occurs. 
 
7.42 
Definitions of DLT 
 
Toxicity will be assessed using the NCI CTCAE, version 4.03 unless otherwise 
specified. A DLT is defined as an AE or abnormal laboratory value (assessed as 
possibly, probably or definitely related to the study medication) which occurs ≤ 
28 days following the first dose of MFR (or 1 cycles of therapy, each cycle = 28 
days), and meets any of the criteria listed in Table 7.421.  
 
If a patient experiences toxicity that fulfills the criteria for a DLT during the 
DLT observation window (cycle 1 day 1 through cycle 1 day 28, treatment with 
the study drug will be interrupted and the toxicity will be followed up. Patients 
will be allowed to remain on study if the DLT is resolved within 4 weeks at the 
discretion of the investigator.  Patients will continue on study at the next lowest 
dose level.  If treatment is reduced during the DLT observation window or is 
held for >28 days for any reason, this will be considered a DLT. 
 
 
 

 
28  
ACCRU-GI-1603 
 
 
7.421 
Dose Limiting Toxicities (DLT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TOXICITY  
DLT CRITERIA 
Hematology 
CTCAE grade 4 neutropenia with fever of any 
duration, or grade 4 neutropenia lasting more 
than 5 consecutive days  
CTCAE grade 4 thrombocytopenia lasting more 
than 5 days, or grade 3 with bleeding 
 
CTCAE Grade 3 or 4 neutropenia with fever 
(temperature ≥ 38.5°C)  
Skin and subcutaneous 
tissue disorders 
 
Rash, hand-foot skin reaction or photosensitivity 
CTCAE Grade 3 lasting more than 7 consecutive 
days despite skin toxicity treatment (as per local 
practice) 
Gastro-intestinal 
CTCAE grade≥ 3 nausea or vomiting lasting 
more than or equal to 48 hrs despite optimal anti-
emetic therapy 
CTCAE grade ≥ 3 diarrhea lasting more than or 
equal to 48 hrs despite optimal anti-diarrhea 
treatment 
Hepatobiliary 
CTCAE grade≥ 3 total   bilirubin (excluding any 
elevations caused by mechanical obstruction of 
the biliary tree by tumor or stent blockage) 
CTCAE grade ≥4 ALT (isolated increases in 
AST without concomitant increases in ALT will 
not be considered dose-limiting, because of the 
non-specific nature of AST) 
Serum alkaline phosphatase CTCAE Grade 4 
lasting more than 7 consecutive days 
ECG QTc Interval 
QTc interval ≥ 501 ms on at least two separate 
consecutive ECGs taken 5 min apart 
Renal 
Serum creatinine > 6x ULN 
Non-hematologic events 
Any non-hematological CTCAE grade ≥ 3, 
except for the exclusions noted below 
Other 
Any related toxicity that delays treatment by > 
28 days 
Exceptions to DLT criteria 
CTCAE grade 3 fatigue lasting fewer than 5 days 
CTCAE grade 3 edema lasting fewer than 5 days 
Grade 3 laboratory abnormalities that are 
responsive to oral supplementation or deemed by 
the investigator to be not clinically significant 
CTCAE version 4.03 will be used for all grading.  
Optimal therapy for vomiting or diarrhea will be based in institutional 
guidelines, with consideration of the prohibited medications listed in this 
protocol. 

 
29  
ACCRU-GI-1603 
 
 
 
 
 
7.5 
Phase II - The phase II study in pancreatic cancer will depend on the successful 
completion of the phase I trial, determination of the recommended dose level and 
discussion between PI and co-sponsors of the study. 
 
 
 
7.51 
Following the accrual of the first 6 patients into the phase II portion, we will 
assess for any unexpected serious toxicities (without halting accrual). If >1 of the 
first 6 patients experience grade 5 toxicity at least possibly (possible, probable, 
definite) related to treatment, we will halt accrual and discuss with the sponsors 
alternative dose levels including the possibility to de-escalate to one dose level. 
After reinitiating accrual, the patients who were included in the prior dose level 
cannot be considered for the final analysis and will have to be replaced. 
 
 
 
7.52 
In the Phase II portion of this study, all patients’ tissue samples will be screened 
for HRD and BRCA-like signature, and only those patients with defects will be 
selected for the treatment study.  
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained.  Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects.  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. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1  
Dose Modifications for Rucaparib (Based on Adverse Events in Tables 8.2 and 8.3) 
 
Starting 
Dose 
Level 
1st Dose Modification 
2nd Dose Modification 
600 mg 
BID 
500 mg BID 
400 mg BID 
400 mg 
BID 
300 mg BID 
200 mg BID 
300 mg 
BID 
200 mg BID 
300 mg QD 
200 mg 
BID 
300 mg QD 
200 mg QD 
NOTE: No more than two dose reductions are allowed. 
 
 
 

 
30  
ACCRU-GI-1603 
 
 
8.2  
Dose Modifications for Hematologic Toxicities 
 
 
Worst Toxicity by CTCAE Gradeb, c 
nal- IRI or 5-FUe 
Grade 2 neutropenia 
(ANC < 1500 – 1000 cells/mm3) 
100% of previous dose 
Grade 3 or 4 neutropenia 
(ANC ≤ 1000 cells/mm3) or febrile 
neutropeniaa 
1st occurrence: 
Delay treatmentd until resolved to 
≤ Grade 2, then reduce dose to by 
25%  
2nd occurrence: 
Delay treatmentd until resolved to 
≤ Grade 2, then reduce dose 
another 25% (50% of original 
dose) 
≤Grade 2 thrombocytopenia 
(Grade 2: platelets ≤75,000/mm3 
-50,000/mm3 
If Grade 2: 
100% of previous dose 
 
Grade 3-4 thrombocytopenia: platelets 
<50,000/mm3) 
If Grade ≥3: 
1st occurrence: 
Delay treatmentd until resolved to 
≤ Grade 2, then reduce dose by 
25% 
2nd occurrence: 
Delay treatmentd until resolved to 
≤ Grade 2, then reduce dose 
another 25% (50% of original 
dose) 
 
aConsider the use of G-CSF for patients who experience ≥ Grade 3 neutropenia or febrile 
neutropenia. 
bAnemia: no changes; transfuse as needed. 
cLymphocytopenia: no changes. 
dFor Grade 3 and worse neutropenia and/or platelets, delay all agents (5FU, leucovorin, nal-
IRI and rucaparib) until resolve to ≤ Grade 2. 
eThe dose of the agent (5FU or nal-IRI) that is most likely the cause of the hematologic 
toxicity, as per investigator’s assessment, will be reduced when resuming treatment.     
 
 
 
 

 
31  
ACCRU-GI-1603 
 
 
8.21 
Recommended dose modification for toxicities except ALT/AST/ bilirubin 
 
NCI-CTCAE v4.03a 
Dose Interruption 
Dose Modification b 
Dose for  
Subsequent  
Cycles 
Grade 0 - < 2 
Non-hematologic 
Treat on time 
No change 
 
Grade 2  
Non-hematologic* 
May be held and/or reduced for toxicities not 
adequately controlled by concomitant 
medication and/or supportive care at the 
discretion of the treating investigator. 
If toxicity remains  
≤ Grade 1, dose re-
escalation can be 
considered at the 
discretion of the 
treating investigator. 
Non-hematologic 
    Grade ≥3 (with the 
exception of 
electrolyte 
abnormalities not 
considered 
clinically 
significant by the 
treating physician) 
Delay until ≤ Grade 2 
Reduce by 1 dose level 
 
Permanent 
discontinuation can be 
considered at treating 
investigator’s 
discretion. 
If toxicities return to 
baseline or ≤ Grade 1 
or ≤ Grade 2 severity if 
not considered a safety 
risk for the patient, 
dose re-escalation can 
be considered at the 
discretion of the 
treating investigator.  
a. NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, 
version 4.03 
  
b. Excludes alopecia, non-refractory nausea/vomiting, or diarrhea adequately controlled with 
systemic antiemetic/antidiarrheal medication administered in standard doses according to 
institutional guidelines. 
 
*Grade 2 creatinine elevations are likely to be seen due to potent inhibition of MATE1 and MATE2-
K by rucaparib. Dose modifications of rucaparib for grade 2 creatinine are not needed unless the 
treating physician has concerns that other factors may be contributing to creatinine elevations.  
 
 

 
32  
ACCRU-GI-1603 
 
 
8.22  
Recommended dose modifications/interruptions for elevations in ALT and/or AST 
related to rucaparib 
 
 
NCI-CTCAE 
v4.03a 
Dose Interruptionb 
Dose Modification 
Dose for  
Subsequent  
Cycles 
Grade   ≤2 
 
Treat on time 
No change 
 
Grade ≥3  
 
• Treat on time 
• Monitor liver 
function tests weekly 
until resolution to ≤ 
Grade 2 
No change, provided 
bilirubin is < ULN and 
alkaline phosphatase is < 3 
x ULN. 
If toxicity remains and 
levels do not decline 
within 2 weeks or they 
continue to rise, 
treatment interruption 
and resolution to ≤ 
Grade 2 is required 
before rucaparib can 
be resumed, either at 
the current dose or a 
reduced dose. 
Grade ≥4 
• Hold rucaparib 
• Monitor liver 
function tests weekly 
until resolution to ≤ 
Grade 2 
 
Resume with a dose 
reduction and monitor 
liver function tests 
weekly for 3 weeks 
after restarting. 
a. NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse 
Events, version 4.03 
  
b. Treatment with rucaparib should be held until the toxicity resolves to ≤ CTCAE Grade 2. 
Twice daily dosing may then be resumed at either the same dose or a lower dose, per 
investigator discretion. If treatment is resumed at the same dose, and the patient experiences 
the same toxicity, the dose should be reduced following resolution of the event to ≤ CTCAE 
Grade 2. If the patient continues to experience toxicity, additional dose reduction steps are 
permitted; however, the investigator should contact ACCRU (see Protocol Resource page) 
before reducing to 300 mg BID. If a patient continues to experience toxicity despite dose 
reduction steps to 300 mg BID, or if dosing with rucaparib is interrupted for > 14 consecutive 
days due to toxicity, treatment should be discontinued, unless otherwise agreed between the 
investigator and ACCRU. 
 
 
 
 
 

 
33  
ACCRU-GI-1603 
 
 
8.3 
Dose Modifications for Non-Hematologic Toxicities Other than grade 3 ALT/AST (follow 
recommendation by Table 8.22), Fatigue and Grade 3 Anorexiaa, d  
 
Worst Toxicity by CTCAE 
Grade* 
na1-IRI 
5-FU 
Grade 1 diarrheab 
Continue same dose 
Continue same dose 
Grade 1 or 2 including diarrhea 
(except alopecia, nausea and 
vomiting) 
Withhold nal-IRI then resume 
once resolved to grade 1 at 
100% of previous dose 
Withhold 5-FU, then resume 
once resolved to grade 1 at 
100% of previous dose, except 
for Grade 2 hand foot syndrome, 
Grade 2 cardiac toxicity, or any 
grade neurocerebellar toxicity 
Grade 3 or 4, including diarrheac 
(except alopecia, nausea and 
vomiting) 
Withhold nal-IRI then resume 
once resolved to grade 1 per 
below: 
1st occurrence: 
Reduce dose to by 25%   
2nd occurrence: 
Reduce dose another 25% (50% 
of original dose) 
Withhold 5-FU then resume 
once resolved to grade 1 per 
below:  1st occurrence: 
Reduce dose by 25% 
2nd occurrence: 
Reduce dose another 25%  
(50% of original dose)d 
*except for Grade 3 or 4 hand 
foot syndrome 
Grade 3 or 4 nausea and/or 
vomiting, despite anti-emetic 
therapy 
Optimize anti-emetic therapy 
AND reduce dose to 50 mg/m2, 
if starting dose is 70 mg/m2.. If 
the patient is already receiving 
50 mg/m2, reduce dose to 43 
mg/m2, c 
Optimize anti-emetic therapy 
AND reduce dose by 25%; if the 
patient is already receiving a 
reduced dose, reduce dose an 
additional 25%e 
Grade 2 hand foot syndrome 
100% of previous dose 
1st occurrence: 
Reduce dose by 25% 
2nd occurrence: 
Reduce dose another 25%  
(50% of original dose)d 
Grade 3 or 4 hand foot 
syndrome 
1st occurrence: 
Reduce dose to 50 mg/m2, if 
starting dose is 70 mg/m2.  
2nd occurrence: 
Reduce dose to 43 mg/m2 
Discontinue therapy 
Any grade neurocerebellar or ≥ 
Grade 2 cardiac toxicity 
No dose modifications requiredd 
Discontinue therapy 
Sensory neuropathy 
No dose modifications requiredd 
No dose modifications requiredd  
* Located at 
   
a Fatigue and Grade 3 anorexia do not require dose modification. 
b Grade 1 diarrhea: 2-3 stools/day > pretreatment. 
c Grade 2 diarrhea: 4-6 stools/day > pretreatment; Grade 3 diarrhea: 7-9 stools/day > pretreatment; Grade 
4 diarrhea: > 10 stools/day > pretreatment. 
d Any toxicity ≥ Grade 2, except anemia and alopecia, can justify a dose reduction if medically indicated. 
e Patients who require more than 2 dose reductions must be withdrawn from the study. 
 
 

 
34  
ACCRU-GI-1603 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician.  NOTE: 5-HT3 
antagonists is specifically recommended as an antiemetic for rucaparib, however, patients 
can be treated per the treating site’s institutional guidelines.  
 
9.2 
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 (ASCO), 
Recommendations for the Use of WBC Growth Factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update. J Clin Oncol 2015;33:3199-3212.  
 
9.3 
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. 
 
9.4 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). Treating physicians can consider administering intravenous 
or subcutaneous atropine 0.25-1 mg (unless clinically contraindicated) for early onset 
diarrhea or any severity. 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 

 
35  
ACCRU-GI-1603 
 
 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site: 
     
 
a. Adverse event monitoring and reporting is a routine part of every clinical trial.   
b. Identify the grade and severity of the event using the CTCAE version 4.0 
c. Determine whether the event is expected or unexpected (see Section 10.2).  
d. Determine if the adverse event is related to the study intervention (agent, 
treatment or procedure) (see Section 10.3). 
e. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
f. Determine if other reporting is required (see Section 10.5). 
g. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA Lowest 
Level Term (LLT). 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
 
Unexpected adverse events or suspected adverse events are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 

 
36  
ACCRU-GI-1603 
 
 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical 
treatment or procedure, the following attribution categories are 
utilized: 
 
Definite - The adverse event is clearly related to the agent(s)/treatment. 
Probable - The adverse event is likely related to the agent(s)/treatment. 
Possible - The adverse event may be related to the agent(s)/treatment. 
Unlikely - The adverse event is doubtfully related to the agent(s)/treatment. 
Unrelated - The adverse event is clearly NOT related to the agent(s) 
treatment. 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug/device and the adverse event.  
 
10.31  Special Situations for Expedited Reporting 
 
 
10.311EXPECTED Serious Adverse Events: Protocol Specific 
Exceptions to Expedited Reporting   
For Phases I and Ib of this study, all Serious Adverse Events will be 
subject to Expedited Reporting (as defined in Section 10.41). The list of 
Expected Serious Adverse Events and associated grades will be reviewed 
and determined by the study team after the completion of the Phase 1b 
portion of the study. 
 
 
10.312 Death 
 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
 
• 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
 

 
37  
ACCRU-GI-1603 
 
 
• 
Death Neonatal:  A disorder characterized 
by cessation of life during the first 28 days 
of life. 
• 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with 
Grade 5. 
• 
Sudden death NOS:  A sudden (defined as 
instant or within one hour of the onset of 
symptoms) or an unobserved cessation of life 
that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Death due to progressive disease should be 
reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (including cysts 
and polyps) – Other (Progressive Disease)” 
under the system organ class (SOC) of the 
same name.  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. 
10.313 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. 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE to be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., acute 
myeloid 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. 
 
10.314 Second Malignancy 
 

 
38  
ACCRU-GI-1603 
 
 
• 
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. 
 
10.315 Pregnancy  
If a patient becomes pregnant during the study the investigator is to stop 
dosing with study drug(s) immediately. 
A pregnancy is not considered to be an AE or SAE; however, any 
pregnancy occurring in a study patient or partner of a study patient 
during study participation or within 6 months of last dosing must be 
reported within the same timelines as an SAE. 
A pregnancy should be followed through to outcome, whenever possible.  
Prior to obtaining private information about a pregnant woman and her 
infant, the investigator must obtain consent from the pregnant woman 
and the newborn infant’s parent or legal guardian before any data 
collection can occur.  A consent form will need to be submitted to the 
IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion the mother is the patient. 
In cases where the child/fetus experiences a serious adverse event other 
than fetal death, the child/fetus is the patient. 
 
NOTE: When submitting the MedWatch 3500A Form for “pregnancy,” 
“pregnancy loss,” or “neonatal loss,” the potential risk of exposure of the 
fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available 
medical documentation.  
 
 

 
39  
ACCRU-GI-1603 
 
 
 
 
10.4  
Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND/IDE trial within 30 Days of the Last Administration of a Commercial Agent 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor 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 sponsor 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 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via MedWatch within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-
hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious 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 within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
 

 
40  
ACCRU-GI-1603 
 
 
Special Instructions: 
• An increased incidence of an expected adverse event (AE) is based on the patients treated for this 
study at their site.  A list of known/expected AE’s are reported in the package insert or the 
literature, including AE’s resulting from a drug overdose. 
 
• Follow site-specific reporting guidelines. 
 
• 
Submit MedWatch form 3500A 
or found on the ACCRU web site) along with the MedWatch 
Fax Cover Sheet (found on the ACCRU web site) to ACCRU Safety via 
email at: 
ACCRU Safety will forward to 
Ipsen and Clovis, as follows: 
 
 
 Clovis: email 
or FAX: 
  
NOTE:  SAE’s must be sent to Clovis within 24 hours of receipt by ACCRU.  
Pregnancies must be reported within 48 hours of receipt by ACCRU. 
 
 Ipsen: email 
 
 
• ACCRU Safety will forward to ACCRU IND Coordinator 
as 
appropriate. The ACCRU IND Coordinator will assist the sponsor-investigator in notifying the 
FDA if required.  
 
• Clovis AEs of Special Interest (AESI) for Rucaparib 
AESI (serious or non-serious) are defined as AEs of scientific and medical concern specific to 
rucaparib, for which ongoing monitoring and rapid communication by the Sponsor-investigator to 
Clovis can be appropriate. Such an event might warrant further investigation in order to 
characterize and understand it. Depending on the nature of the event, rapid communication by the 
Sponsor-Investigator to other parties (e.g., regulators) might also be warranted.  AESI’s should be 
reported within 24 hours of awareness to the ACCRU SAE Coordinator using the MedWatch 
form 3500A.  Within 24 hours, the ACCRU SAE Coordinator will report to Clovis 
 
 
 
Clovis AEs of Special Interest for this trial include: 
 
1. 
Leukemia secondary to oncology chemotherapy (e.g. Acute Myeloid Leukemia 
[AML] 
2. 
Myelodysplastic syndrome (MDS) 
3.  
Pneumonitis 
 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 

 
41  
ACCRU-GI-1603 
 
 
 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events.  In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
If the event meets the criteria for an UPIRTSO, submit to your IRB as required 
by your institutional policies.   
 
10.52 Baseline and Adverse Events Evaluations 
 
“Investigators should complete all routine and standard of care assessments to 
evaluate for toxicity and symptoms of drug-induced adverse events. This may 
include, but is not limited to, verbal reports from the patient and/or caregiver, 
physical examination and laboratory findings. Adverse events should be reported 
throughout the course of the study, until the study termination visit, and followed 
through to resolution”.  
 
 

 
42  
ACCRU-GI-1603 
 
 
10.521 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline per the CTCAE v4.0 
grading: 
 
System Organ 
Class 
Adverse Event 
Symptom(s) 
Baseline 
Each Evaluation 
Blood and 
lymphatic system 
disorders 
Febrile 
neutropenia 
 
X 
Gastrointestinal 
# stools per day 
X 
 
Diarrhea 
 
X 
Nausea  
X 
X 
Vomiting 
X 
X 
General disorders 
and 
administration site 
conditions  
Edema limb 
X 
X 
Periorbital edema 
 
X 
 
X 
Fatigue 
X 
X 
Investigations 
Aspartate 
aminotransferase 
(AST) increase 
X 
X 
Alanine 
aminotransferase 
(ALT) increase 
X 
X 
Alkaline 
phosphatase, 
serum (ALK) 
increase 
X 
X 
Blood Bilirubin 
increase 
X 
X 
Neutrophil count 
decrease 
X 
X 
Platelet count 
decrease 
X 
X 
Metabolism and 
nutrition disorders 
Hypokalemia 
X 
X 
Renal and urinary 
disorders 
Serum creatinine 
increase 
X 
X 
 
 
 
 

 
43  
ACCRU-GI-1603 
 
 
10.53  Submit via appropriate Academic and Community Cancer Research United 
(ACCRU) Case Report Forms (i.e., paper or electronic, as applicable) the 
following AEs experienced by a patient and not specified in Section 10.5:  
 
10.531 Phase I/Ib:  
 
 
 
All AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure, regardless of Grade 
 
10.532 Phase II:  
 
 
Grade 1-2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
 
 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
 
 
10.54 Grade 5 AEs (Deaths) 
 
 
 
10.541 Any death ≤30 days of the patient’s last study treatment or procedure 
regardless of attribution to the study treatment or procedure. 
 
10.542 Any death >30 days after the patient’s last study treatment or procedure 
that is felt to be at least possibly treatment related must also be 
submitted as a Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
 
10.55   Refer to the instructions in the CRF Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
10.56 Reconciliation: Clovis will send Research Coordinating Center a monthly listing 
of SAEs received by Clovis from Research Coordinating Center in connection 
with the Trial and any SUSARs sent to Research Coordinating Center from 
Clovis. Research Coordinating Center will review the listing and notify Clovis of 
any omissions. 
 
10.57 Quarterly Report: Research Coordinating Center will provide Ipsen with accrual 
and a toxicity report on a quarterly basis. 
 
11.0 
Treatment Evaluation Using RECIST Guideline 
 
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 (Eisenhauer EA, Therasse P, Bogaert J, et al., 2009)).  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. 
 

 
44  
ACCRU-GI-1603 
 
 
11.1 
Schedule of Evaluations:  For the purposes of this study, patients should be reevaluated 
every 8 weeks.   
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21   Measurable Disease 
 
11.211 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, CT component of a PET/CT, or MRI.  
 
11.212 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) or 
imaging.  
 
11.213 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).   
 
 
NOTE: Tumor lesions in a previously irradiated area are considered measurable 
disease under the following conditions:   
• 
Tumor lesions in a previously irradiated area are considered target 
lesions only if they have progressed after XRT and prior to start this 
investigational protocol. 
 
11.22 Non-Measurable Disease 
 
11.221 All other lesions (or sites of disease) are considered non-measurable 
disease, including pathological nodes (those with a short axis ≥1.0 to <1.5 
cm).  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-
measurable as well. 
 
Note:  ‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are present 
in the same patient, these are preferred for selection as target lesions.  In 
addition, lymph nodes that have a short axis <1.0 cm are considered non- 
pathological (i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 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 follow-

 
45  
ACCRU-GI-1603 
 
 
up. 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.  
 
11.32 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. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.     
 
• 
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. 
 
 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’  New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
 
b.   No FDG-PET at baseline and a positive FDG-PET at follow-up:   
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.   
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans 8 weeks after the prior CT) are 
needed to determine if there is truly progression occurring at that site. 
In this situation, the date of PD will be the date of the initial abnormal 
PDG-PET scan.   
 
iii If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 
 
11.33 Measurement at Follow-up Evaluation:   

 
46  
ACCRU-GI-1603 
 
 
 
• 
A subsequent scan must be obtained 8 weeks following initial documentation 
of an objective status of either complete response (CR) or partial response 
(PR).  
 
• 
In the case of stable disease (SD), follow-up measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 8 weeks 
(see Section 11.44). 
 
• 
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. 
 
• 
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 Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) 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 11.21), 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 

 
47  
ACCRU-GI-1603 
 
 
(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. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) 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 
11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI/PET-CT/Chest X-ray/physical examination 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, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
11.432 Evaluation of Target Lesions 
 
• Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have 
reduction in short axis to <1.0 cm. 
 
 
• 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 
11.41). 
 

 
48  
ACCRU-GI-1603 
 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. 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.  
 
b. 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 (Section 11.41).  In addition, the 
PBSD must also demonstrate an 
absolute increase of at least 0.5 cm 
from the MSD.  
 
c. See Section 11.32 for details in 
regards to the requirements for PD via 
FDG-PET imaging. 
  
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all non-target 
lesions.  
 
b. Each non-target lymph node must 
have a reduction in short axis to <1.0 
cm. 
 
 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. 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.   
 

 
49  
ACCRU-GI-1603 
 
 
b. 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.)  
   
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 
 
 

 
50  
ACCRU-GI-1603 
 
 
11.44 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 tables:  
 
 
For Patients with Measurable Disease  
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target 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 11.431 
** NOTE:  This study uses the protocol RECIST v1.1 template dated 2/16/2011.  For data collection 
and analysis purposes the objective status changed from SD to PR in the ACCRU protocol RECIST 
v1.1 template as of 2/16/2011 and to match RECIST v1.1 requirements. 
 
11.45 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 PD due to “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
12.0 
Descriptive Factors   
 
• 
Phase I/Ib/II, ECOG PS: 0 vs. 1 
• 
Phase I only, dose level: -2 vs. -1 vs. 1 vs.2-A vs. 2-B vs. 3 
 
 
 

 
51  
ACCRU-GI-1603 
 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
 
13.1 
Patients who are CR, PR, or SD will continue treatment per protocol. 
 
Patients who are CR, PR, or SD at time of their reassessment and have not experienced 
intolerable toxicity will be allowed to continue protocol treatment at the same dose level 
until PD or maximum of 3 years whichever is earlier. 
 
 
Those patients who are CR, PR, or SD but have experienced unacceptable toxicity may 
be eligible for retreatment at a lower dose until PD or maximum of 3 years whichever is 
earlier, at discretion of treating physician (see Section 8.0). 
 
13.2 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
Treatment decision during event-monitoring phase is at the discretion of the treating 
physician. 
 
13.3 
Patients who go off protocol treatment for reasons other than PD will go to the event-
monitoring phase per Section 18.0. Treatment decision during event-monitoring phase is 
at the discretion of the treating physician. 
 
13.4  
If a patient enrolled to Phase I dose escalation part of the study fails to complete the 
initial course of therapy (defined as drug administration ≤ 75% of expected cycle 1 total 
dose) for reasons other than dose-limiting toxicity defined adverse events, the patient will 
be regarded as uninformative in regard to the primary study goal and an additional patient 
will be enrolled at the current dose level 
 
 
13.5 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 
18.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. 
Event monitoring will be required per Section 18.0 of the protocol.  
  
13.6 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
 
13.7 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  The patient will go directly to the event-
monitoring phase of the study, and event monitoring will be required per Section 18.0 of 
the protocol.

 
52  
ACCRU-GI-1603 
 
 
14.0 
Body Fluid Biospecimens   
 
 
14.21 Summary Table of Research Blood/Blood Products to Be Collected for This Protocol 
 
Indicate if 
specimen 
is 
mandatory 
or optional 
Collection 
tube 
description 
and/or 
additive 
(color of 
tube top) 
Volume to 
collect per 
tube 
(number 
of tubes  
to be 
collected) 
Blood 
product 
being 
processed 
and 
submitted by 
participating 
site 
Baseline 
Restaging
2 
End of 
treatment 
(PD, 
removal or 
withdrawal) 
Additional 
processing 
required 
at site 
after blood 
draw? 
Storage 
/shipping 
conditions1 
Mandatory 
None (red 
top) 
10 ml (1) 
Whole blood 
X 
X 
X 
No 
Refrigerate 
(cold 
packs) 
Mandatory 
EDTA 
(purple top) 
10mL  
(1) 
Whole blood 
X 
X 
X 
No 
Refrigerate 
(cold 
packs) 
Mandatory 
STRECK 
(tan and 
black 
marble top) 
10mL         
(1) 
Whole blood 
X 
X 
X 
No 
Ambient 
 
1After all samples have been processed according to kit instructions, ship all specimens according to shipping instructions (see 
 Section 14.25 for detailed shipping instructions.) 
 
2 All Restaging collections of No Additive red top, EDTA purple top and STRECK tan and black top tubes will be noted as “Restaging” 
on kit requisition form. 
 
14.21 Kits are required for this study. 
 
14.211 The kit contains supplies and instructions for collecting, processing, and shipping specimens. 
 
14.212 Participating institutions may obtain kits from the BAP Lab via the Mayo Clinic Research Client Request Portal 
(MCRCRP). Detailed instructions for using MCRCRP are available on the ACCRU website located under the 
study specific ‘Manuals and Forms’. Because we are now being charged for all outgoing kits, a small, but 

 
53  
ACCRU-GI-1603 
 
 
sufficient, supply of the specimen collection kits should be ordered prior to patient entry. Unused/expired kits 
should be disposed per institution policy. Do not send unused kits back to BAP. Kit requests must be filled in 
completely and accurately for quick processing. For questions regarding your kit order contact 
 
 
NOTE: Expired kit tubes may be exchanged with site stock if available.  
 
14.213 Kits will be sent via FedEx® Ground at no additional cost to the participating institutions.  Allow at least two 
weeks to receive the kits.   
 
14.214 Kits will not be sent via rush delivery service unless the participating institution provides their own FedEx® 
account number or alternate billing number for express service.   
 
NOTE: ACCRU will not cover the cost for rush delivery of kits. 
 

 
54  
ACCRU-GI-1603 
 
 
 
14.22 All samples must be collected Monday-Friday. 
 
14.23 Label specimen tube(s) with protocol number, ACCRU patient ID number, and 
time and date blood is drawn. 
 
14.24 Collect and process all blood/blood products according to specific kit instructions 
and table below.  
 
14.25 Shipping 
 
14.251 Verify ALL sections of the Specimen Submission: Blood form (see CRF 
packet), BAP Requisition Form (provided in kit), and specimen 
collection labels are completed and filled in correctly.    
 
14.252 Specimens must be shipped the same day they are drawn. 
 
14.253 Specimens will be shipped in a dual-temperature shipping container.  
Place the refrigerated EDTA, No Additive tubes with a properly 
prepared cold pack in one compartment.  See kit instructions for specific 
details for cold pack preparation (i.e., frozen or refrigerated) and proper 
packing of blood and cold pack to avoid freezing of specimen.   Place the 
STRECK tube in the ambient compartment of the dual-temperature 
shipping container. 
 
14.254 Ship specimens via Priority Overnight service, Monday – Friday, to 
BAP Receiving according to kit instructions.  Do not send samples on 
weekends or just prior to federal holidays. 
 
14.255 The BAP kits will include a smart shipper label (3x5 white barcoded 
label) affixed to the shipping boxes.  The smart shipper label is a pre-
addressed return label, which replaces the need for an air bill.  Shipping 
costs will be covered by ACCRU if the shipping box provided with the 
BAP kit is used for shipping specimens to BAP Receiving.  
 
Ship samples to:      
       
  
 
  
   
 
14.256 BAP Freezer will receive the samples.   
 
 

 
55  
ACCRU-GI-1603 
 
 
14.3 
Study Methodology and Storage Information 
 
14.31 Blood/blood product samples will be collected for the following research  
 
14.311 DNA extraction and storage of DNA and buffy coats for future 
pharmacogenetic assays that may correlate with efficacy and tolerability.  
using standard laboratory protocols.  DNA/serum/plasma will be sent to 
a Clovis 3rd party diagnostic collaborator for genomic analysis. 
Remaining DNA and buffy coats will be stored frozen at -70ºC by BAP, 
according to patient consent information until specific analyses are 
identified.  As protocols are developed, they will be presented for 
ACCRU and IRB review and approval.  (This collection is part of a 
general strategy of investigation for the majority of ACCRU studies.) 
 
14.312 As part of ongoing ACCRU research, we will collect serum/plasma for 
future research studies, according to patient consent information, on 
molecular determinants of efficacy and tolerability.  Samples will be 
stored frozen at -70ºC by BAP until specific analyses are identified.  As 
protocols are developed, they will be presented for ACCRU and IRB 
review and approval.   
 
14.4 
Return of Genetic Testing Research Results 
 
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
 
If at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA-certified setting will be required.  Sharing of 
research data with individual patients should only occur when data have been validated 
by multiple studies and testing has been done in CLIA-approved laboratories. 
 
15.0 
Drug Information 
 
 
IND exempt 
 
15.1 
Rucaparib PO 
 
• 
Investigator brochure available on the ACCRU web site. 
 
15.11 Background: Rucaparib camsylate is available for oral administration. 
Rucaparib is a potent small molecule inhibitor of poly-adenosine diphosphate 
(ADP) ribose polymerase (PARP) enzymes, including PARP-1, PARP-2, and 
PARP-3. These proteins play an important role in the repair of DNA in cells. 
Some cancer cells, including those with a mutation in the BRCA gene, are 
particularly dependent on PARPs to repair damaged DNA because they lack 
other proteins for repairing DNA that normal cells have.  
 
 

 
56  
ACCRU-GI-1603 
 
 
 
By blocking the activity of PARPs in cancer cells, rucaparib is expected to stop 
the cancer cells from being able to repair damaged DNA. This eventually leads to 
the death of the cancer cells, thereby slowing down the growth of the cancer. 
 
15.12 Formulation: The oral formulation of rucaparib contains the camphorsulfonic 
acid salt of the active agent rucaparib. All dosage strengths are expressed as the 
weight of free base rucaparib. Three strengths of oral rucaparib 200 mg, 250 mg, 
and 300 mg are available as immediate release film-coated tablets.  The 200 mg, 
250 mg, and 300 mg tablets all contain the same ratios of active agent and 
excipients, with different strengths achieved by increasing the total amount of 
material.  The physical appearances of the tablets are unique in order to ensure 
proper identification. The 200 mg tablets are blue, round (11 mm) tablets de-
bossed with ‘C2’. The cosmetic blue film coating is Opadry II containing 
polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, talc, FD&C 
Blue #1 colorant, brilliant blue FCF aluminum lake, and FD&C blue indigo 
carmine aluminum lake. The 250 mg tablets are white, diamond shaped (15 mm 
x 11 mm) tablets de-bossed with ‘C25’. The cosmetic white film coating is 
Opadry II containing polyvinyl alcohol, titanium dioxide, polyethylene 
glycol/macrogol, and talc. The 300 mg tablets are yellow, oval tablets (16 mm x 
8 mm) de-bossed with ‘C3’. The cosmetic yellow film coating is Opadry II 
containing polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, 
talc, and irradiated yellow iron oxide.   
 
15.13 Preparation and storage: Tablets are provided in high-density polyethylene 
(HDPE) bottles with child-resistant caps and should be stored in the provided 
containers. Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 
30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 
 
  
15.14 Administration:  The effect of food is not clinically significant, therefore, 
rucaparib may be taken with or without food. 
 
 
15.15 Pharmacokinetic information: 
 
AUC: 4120 (ng*h/mL) 
Bioavailability: 36% 
Plasma protein binding: 55%-75% 
Distribution: 113-262L, indicating distribution into tissues. 
 
Half-life elimination: 9.23-33.6hours 
 
Cmax: 274 ng/mL 
Tmax: 1.5-64 hours  
Excretion: Urine samples collected for 24 hours after a single test dose 
resulted in 10.5% of the dose being recovered.  This result indicates renal 
elimination is not the major elimination pathway. 
 
15.16 Potential Drug Interactions:   
 
Enzymes responsible for rucaparib metabolism have not been identified. 
Based on in vitro data, CYP2D6, and to a lesser extent CYP1A2 and 
CYP3A4, were able to metabolize rucaparib. In population PK analysis, 

 
57  
ACCRU-GI-1603 
 
 
patients with different CYP2D6 or CYP1A2 genotypes showed 
comparable rucaparib PK. Although in vitro rucaparib metabolism 
mediated by CYP3A4 was slow, a significant contribution of CYP3A4 in 
vivo cannot be excluded. Caution should be used for concomitant use of 
strong CYP3A4 inhibitors or inducers.  
 
Clinical results indicated that rucaparib, at 600 mg BID, moderately inhibited 
CYP1A2, weakly inhibited CYP2C9, CYP2C19, CYP3A, and BCRP, and 
showed no clinically significant effect on P-gp. Caution should be exercised in 
the concomitant use of drugs that are substrates of the above CYP enzymes 
with narrow therapeutic windows. Rucaparib also caused mild increases in 
plasma exposure to oral contraceptives (ie, ethinylestradiol and levonorgestrel). 
 
CYP1A2 Substrates 
When co-administering medicinal products metabolized by CYP1A2, 
particularly medicines which have a narrow therapeutic index (eg, 
tizanidine, theophylline), dose adjustments may be considered based on 
appropriate clinical monitoring.  
 
CYP2C9 Substrates 
When co-administering medicinal products that are CYP2C9 substrates 
with a narrow therapeutic index (eg, warfarin, phenytoin), dose 
adjustments may be considered, if clinically indicated. Exercise caution 
and consider additional INR monitoring with co-administration of warfarin 
and therapeutic drug level monitoring of phenytoin, if used concomitantly 
with rucaparib.  
 
CYP2C19 Substrates 
No dose adjustment is considered necessary for co-administered medicinal 
products that are CYP2C19 substrates.  
 
CYP3A Substrates 
Caution is advised when co-administering medicinal products that are 
CYP3A substrates with a narrow therapeutic index (eg, alfentanil, 
astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine). Dose 
adjustments may be considered, if clinically indicated based on observed 
AEs.  
 
P-gp Substrates 
No dose adjustment is recommended for co-administered medicinal 
products that are P-gp substrates. 
BCRP Substrates 
No dose adjustment is recommended for co-administered medicinal products that 
are BCRP substrates. 
 
Oral Contraceptives 
Co-administered rucaparib could increase plasma exposures of oral 
contraceptives.  The effect is mild and no dose adjustment is recommended for 
oral contraceptives. 

 
58  
ACCRU-GI-1603 
 
 
 
Other Enzymes and Transporters 
Interaction of rucaparib with other enzymes and transporters was evaluated in 
vitro. Rucaparib is a weak inhibitor of CYP2C8, CYP2D6, and UGT1A1. 
Rucaparib down regulated CYP2B6 in human hepatocytes at clinically relevant 
exposures. In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-K, a 
moderate inhibitor of OCT1, and a weak inhibitor of OCT2. As 
inhibition of these transporters could decrease renal elimination and liver uptake 
of metformin, caution is advised when metformin is co-administered with 
rucaparib. 
 
 
15.17 Known potential adverse events:  
 
Common known potential toxicities (> 10%):   
 
Asthenia, fatigue, anemia, increased ALT/AST, thrombocytopenia, nausea, 
vomiting, diarrhea, increased serum creatinine, decreased appetite, 
constipation, abdominal pain, dyspepsia, dysgeusia, dizziness, dyspnea, 
pyrexia, insomnia, photosensitivity reaction 
 
Less common known potential toxicities (1% - 10%):  
 Leukopenia, lymphopenia, decreased WBC, increased serum cholesterol, 
hypercholesterolemia, increased transaminases, decreased lymphocyte 
count, decreased neutrophil count, hypophosphatemia, febrile neutropenia, 
upper respiratory tract infection, Myelodysplastic Syndrome, Acute 
Myeloid Leukemia 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
 
Pneumonitis 
 
15.18 Drug procurement 
 
Clovis will provide the commercial formula of rucaparib free of charge to 
Clinical Research Services, a division of Rx Crossroads by McKesson for 
investigational use in this study.  The product will be labeled, “For 
Investigational Use.” Each participating ACCRU treating location will order the 
drug from Clinical Research Services, a division of Rx Crossroads by McKesson. 
It will take 1-2 business days to receive the rucaparib. 
Fax the Drug Order Request Form (found on the ACCRU web site) to:  
 
 
  
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of rucaparib and will use the appropriate Drug Order Request Form to 
order additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 

 
59  
ACCRU-GI-1603 
 
 
at each institution after approval is received by Clovis.  The Clovis IP 
Destruction Authorization Form should be completed by each site and submitted 
to Clinical Research Services, a division of Rx Crossroads by McKesson 
   Clinical 
Research Services, a division of Rx Crossroads by McKesson will submit form to 
Clovis for drug destruction approval on-site.  The Clovis IP Destruction 
Authorization Form should also be used to report drug that is to be destroyed 
due to damage or out of temperature specifications (temperature excursions) to 
Clinical Research Services, a division of Rx Crossroads by McKesson , who will 
then send to Clovis. 
 
 
15.19 Nursing Guidelines:  
 
15.191 Common GI side effects include abdominal pain, constipation, nausea, 
vomiting, diarrhea, and decreased appetite. Manage symptomatically and 
monitor for effectiveness of intervention. 
 
15.192 Monitor CBC w/differential. Cytopenias are common, especially when 
given with other chemotherapy. Instruct patients to report any signs or 
symptoms of infection or bleeding to the study team. 
 
15.193 Fatigue can be seen. Instruct patient in energy conserving lifestyle. 
 
15.194 Dizziness and headache can be seen. Treat symptomatically. 
 
15.195 Monitor LFT’s. 
 
15.196 (For PO formulation) Rucaparib may be given with or without food. 
Patients should be instructed to take agent with at least 8 oz of room 
temperature water.  
 
15.197 There are several drug to drug interactions, patients who are on other 
concomitant medications that are CYP substrates. Extra monitoring may 
be required for patients who are on agents with narrow therapeutic 
ranges (i.e warfarin).  Assess patient’s medication lists carefully 
including OTC and herbal products. 
 
15.198 Rarely palmar-plantar erythrodysesthesia (hand-foot syndrome) may be 
seen.  Instruct patients to use moisturizers, and to protect hands and feet.  
 
15.199 May cause photosensitivity.  Instruct patients to use good photo 
protection, including limiting sun exposure and using sunscreen. 
 
15.199a Rarely patients can develop myelodysplastic syndrome or AML. 
 
15.199b Pneumonitis has been seen. Instruct patients to report any shortness of 
breath, new cough, dyspnea on exertion, or chest pain to the study team. 
 
 
15.2 
MM-398 (nal-IRI, Onivyde®, Irinotecan Liposome Injection, PEP02) 
 
 

 
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• 
Investigator brochure available on the ACCRU web site. 
 
15.21 Background:   The formulation of irinotecan liposome injection was invented by 
Hermes Biosciences, Inc. (South San Francisco, CA), developed by 
PharmaEngine, Inc., and subsequently acquired by Merrimack Pharmaceuticals, 
Inc. In April 2017 Ipsen acquired this asset from Merrimack. Currently, Ipsen 
and Servier (previously Shire) are co-developing irinotecan liposome injection. 
Ipsen is solely responsible for commercializing irinotecan liposome injection in 
the United States.  
 
 
Drug carrier technologies represent a rational strategy to improve the 
pharmacokinetics and biodistribution of irinotecan while protecting it from 
premature metabolism. Irinotecan liposome injection employs a novel 
intraliposomal drug stabilization technology for encapsulation of irinotecan into 
long-circulating liposomes with high drug load and high in vivo stability. The 
stable liposome formulation of irinotecan has several attributes that may provide 
an improved therapeutic index. The controlled and sustained release should 
improve activity of this schedule-dependent drug by increasing duration of 
exposure of tumor tissue to drug, an attribute that allows it to be present in a 
higher proportion of cells during the more sensitive S-phase of the cell cycle. 
 
 
 
The improved pharmacokinetics, high drug retention in the liposomes, and 
enhanced permeability and retention (EPR) effect may result in site-specific drug 
delivery to solid tumors. Stromal targeting may result from the subsequent depot 
effect, where liposomes accumulate in tumor associated macrophages (TAMs) 
which release the active drug, irinotecan, and contribute to local conversion to be 
substantially more cytoxic SN-38, the active metabolite of irinotecan. The 
preferentially local biotransformation should result in reduced exposure to 
potential sites of toxicity and increased exposure to neighboring cancer cells 
within the tissue. 
 
15.22 Formulation: Irinotecan liposome is supplied as a sterile solution containing 
4.33 mg/ml of irinotecan on the free base basis (equivalent to 5 mg/ml of 
irinotecan hydrochloride trihydrate) encapsulated in liposomes. The drug product 
is a sterile, white to slightly yellow opaque isotonic liposomal dispersion for 
intravenous infusion. Each vial has a nominal fill volume of 10 mL with an 
overfill of approximately 0.5 mL. Each vial is intended for single use IV 
administration only. 
 
15.23 Preparation, storage, and stability: Irinotecan liposome must be 
refrigerated at 2°C-8°C (36°F-46°F). Do not freeze. Protect from light. 
Irinotecan liposome injection is a cytotoxic drug. Follow applicable special 
handling and disposal procedures (including for shelf life). Prior to 
administration, irinotecan liposome injection must be diluted in 5% 
Dextrose injection or 0.9% Sodium Chloride, or per protocol-specific 
directions. The solution for infusion should be used immediately, but may 
be stored at room temperature (15º to 25ºC) for up to 4 hours . If 
necessary, the solution for infusion may be refrigerated (2º to 8ºC) for no 
more than 24 hours prior to use. The solution for infusion must not be 
frozen as the liposome structure will be disrupted, resulting in the 

 
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ACCRU-GI-1603 
 
 
premature release of irinotecan. Irinotecan liposome has been tested for 
compatibility with limited materials, and no compatibility issues have been 
identified. 
 
15.24 Administration:  Irinotecan liposome is administered over 90 minutes or as 
directed per protocol.  Do not use in-line filters. Infusion sets without in-line 
filters are recommended for use. However, an infusion set with an in-line filter 
that has a pore size of at least 0.2 microns is compatible for use. 
 
 
 
 
15.25 Pharmacokinetic information: 
Distribution: The volume of distribution (Vd) estimates in patients 
administered irinotecan liposome were 2.2 L/m2. 
Protein Binding:  <1% Metabolism: Information about the metabolism 
and excretion of irinotecan relies on information from the physician’s 
package insert for Camptosar®  
Half-life elimination: total irinotecan: ~ 26 hours; SN-38:  ~68 hoursRace: 
Following the administration of irinotecan liposome injection, race was  
strongly associated with total irinotecan exposure. In the last updated PopPK 
analysis (excluding the study in Japanese patients), irinotecan clearance was 80% 
higher in patients of Asian ethnicity than other populations. In the PopPK model 
including the Japanese, exposure of total and converted SN-38 were 
approximately 30% and 25% higher respectively than those observed in non-
Japanese subjects. This finding suggests that the higher clearance of total 
irinotecan in Asians resulted in higher converted amount to SN-38. Despite the 
observed differences by race for SN-38 exposure, myelosuppression and 
diarrhea, the degree of difference is not clinically substantial to suggest that dose 
modification by race would be needed. 
 
15.26 Potential Drug Interactions:   
Information about the drug interactions of irinotecan liposome relies on 
information from the physician’s package insert for Camptosar®, which 
states that irinotecan and its active metabolite, SN-38, are metabolized via 
CYP3A4 and UGT1A1, respectively.  Data from the phase 2 clinical 
safety study PEP0206 supported the similarity in the metabolic fate of 
irinotecan released from nal-IRI and from direct administration with 
Camptosar®. 
The concentrations of 5-FU measured in the study NAPOLI-1 were consistent 
with the difference in the two 5-FU dose regimens. Therefore, no effects are 
expected of irinotecan liposome injection administration on 5-FU 
pharmacokinetics. 
Based on population pharmacokinetic analysis, no significant association was 
observed between the pharmacokinetic parameters of total irinotecan and SN-38 
following irinotecan liposome injection monotherapy and when co-administered 
with 5-FU/LV. This result is consistent with the lack of drug interaction noted 
between irinotecan and 5-FU. 
 
15.27 Known potential toxicities: The safety of irinotecan liposome, a liposomal 
formulation of irinotecan, may be indirectly compared with the safety of 

 
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irinotecan, primarily based on a qualitative comparison of adverse reactions, as 
reported in the Camptosar US Product label for irinotecan, and as summarized in 
this document and reflected in the US Product Label for irinotecan liposome 
injection. The comparison is qualitative, since both irinotecan and irinotecan 
liposome injection have been used in different doses and schedules as 
monotherapy and combination therapy with other chemotherapeutic agents; 
making quantitative comparisons are difficult. The most common adverse 
reactions of irinotecan and irinotecan liposome injection are similar and are 
mainly gastrointestinal events and myelosuppression.   
 
 
 
In single agent irinotecan therapy clinical studies, the most common adverse 
reactions (≥30%) observed are: nausea, vomiting, abdominal pain, diarrhea, 
constipation, anorexia, neutropenia, leukopenia (including lymphocytopenia), 
anemia, asthenia, fever, body weight decreasing, and alopecia. 
 
 
 
Comparatively, irinotecan liposome injection, when used in combination with 5-
fluorouracil and leucovorin, the most common adverse reactions (≥20 %) 
observed in clinical trials considered were: diarrhea, fatigue/asthenia, nausea, 
vomiting, decreased appetite, stomatitis, and pyrexia  The most common 
laboratory abnormalities (≥10 % Grade 3 or 4) were lymphopenia and 
neutropenia (ONIVYDE USPI). 
 
 
Certain known adverse reactions of irinotecan have not been observed with 
irinotecan liposome injection to date. This could be due to the limited cumulative 
patient exposure to date of irinotecan liposome injection, or the use of 
appropriate premedication and early recognition and treatment of expected 
adverse events. The adverse reactions observed with irinotecan and not yet 
observed with irinotecan liposome injection include anaphylaxis or anaphylactoid 
reaction, interstitial lung disease-like pulmonary toxicity and acute pancreatitis. 
There is insufficient evidence to know whether these known adverse reactions of 
irinotecan will also be associated with irinotecan liposome injection. 
 
15.28 Drug procurement:   
 
Ipsen will provide the commercial formula of irinotecan liposome free of charge 
to Clinical Research Services, a division of Rx Crossroads by McKesson for 
investigational use in this study. The product will be labeled, “For Investigational 
Use.” Each participating ACCRU treating location will order the drug from 
Clinical Research Services, a division of Rx Crossroads by McKesson. It will 
take 1-2 business days to receive the nal-IRI.  
 
Fax or email the Drug Order Request Form (found on the ACCRU web site) to:  
 
  
  
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of nal-IRI and will use the appropriate Drug Order Request Form to 
order additional supplies as needed. 

 
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ACCRU-GI-1603 
 
 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
 
15.29 Nursing Guidelines:   
 
15.291 If possible, check for any history of hypersensitivity reaction to any 
previous drug formulated with polysorbate 80. 
 
15.292 Cholinergic symptoms of lacrimation, nasal congestion, diaphoresis, 
flushing, ABD cramping, and diarrhea can occur at the beginning, 
during, or immediately after the irinotecan liposome 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 liposome 
infusion.  If diarrhea occurs within one hour of infusion, refer to Section 
9.2 or 15.16 for management.  
 
15.293 Patient education is extremely important.  Impress on the patient the 
importance of compliance with treatment of diarrhea management (see 
Section 9.4).  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. 
 
15.294 Ondanestron 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. 
 
15.295 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. 
 
15.296 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/m (median 750).  Instruct patient to report any cough 
or SOB. 
 
15.297 Patients are at risk for developing eosinophilia and will improve on 
steroid therapy. 
 
15.298 Hepatic enzyme elevations have been transient and did not require 
intervention. 
 
15.299a 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. 
 
15.299b Advise patients of probable hair loss. 
 

 
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15.3 
Fluorouracil (Adrucil, Efudex, [5-FU]) 
 
• 
Refer to package insert for complete, up-to-date information. 
 
15.31 Background: Antineoplastic Agent, Antimetabolite (Pyrimidine Analog). 
Fluorouracil is a fluorinated Pyrimidine Antimetabolite that inhibits thymidylate 
synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, 
interfering with DNA, and to a lesser degree, RNA synthesis. Fluorouracil 
appears to be phase specific for the G1 and S phases of the cell cycle. 
 
15.32 Formulation: Commercially available for injection 50 mg/mL (10 mL, 20 mL, 
50 mL, and 100 mL). 
 
15.33 Preparation, 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. Dilute in 50 – 1000 
mL of 0.9% NaCl or D5W. 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 coadministered with either diazepam, 
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. 
 
15.34 Administration:  Fluorouracil will be given by continuous IV infusion over 46 
hours.  
 
Refer to section 7.0 (treatment) administration instructions specific to the 
protocol.  
 
 
15.35 Pharmacokinetic information: 
 
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. 
 
 
15.36 Potential Drug Interactions:  Fluorouracil may increase effects of 
warfarin. Avoid ethanol (due to GI irritation). Avoid black cohosh. 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information. 
 
Common known potential toxicities, > 10%:   

 
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ACCRU-GI-1603 
 
 
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. Cerebellar 
ataxia, headache, somnolence, ataxia are seen primarily in intracarotid 
arterial infusions for head and neck tumors.  
 
15.38 Drug procurement:  Commercial supplies. Each participating ACCRU treating 
location shall obtain supplies from normal commercial supply chain or 
wholesaler. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
 
15.39 Nursing Guidelines:  
 
15.391 Monitor complete blood count and platelet count.  Instruct patient to 
report signs and symptoms of infection, unusual bruising or bleeding to 
the physician. 
 
15.392 Administer antiemetics as indicated. 
 
15.393 Diarrhea may be dose-limiting; encourage fluids and treat 
symptomatically. 
 
15.394 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. 
 
15.395 Monitor for neurologic symptoms (headache, ataxia). 
 
15.396 Inform patient of potential alopecia. 

 
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15.397 Those patients on continuous infusion may need instruction regarding 
central intravenous catheters and portable intravenous or intra-arterial 
infusion devices. 
 
15.398 Fluorouracil–induced conjunctivitis is a common problem.  Advise 
patient to report any eye soreness or redness to the healthcare team. 
 
15.399 Photosensitivity may occur.  Instruct patients to wear sun block when 
outdoors. 
 
15.4 
Leucovorin Calcium (CF) 
 
• 
Refer to package insert for complete, up-to-date information. 
 
15.41 Background: A reduced form of folic acid, leucovorin supplies the necessary 
cofactor blocked by methotrexate, enters the cells via the same active transport 
system as methotrexate. Stabilizes the binding of 5-dUMP and thymidylate 
synthetase, enhancing the activity of fluorouracil. 
 
15.42 Formulation: Commercially available as: 
Injection, powder for reconstitution: 50 mg, 100 mg, 200 mg, 350 mg 
Injection, solution: 10 mg/mL (10mL, 30 mL) 
 
15.43 Preparation, storage, and stability:  
Powder for injection: Store at room temperature, protect from light. 
Reconstitute with sterile water for injection or bacteriostatic water for 
injection; dilute in 100-1000 mL 0.9% NaCl or D5W. When doses > 10 
mg/m2 are required, reconstitute using sterile water for injection, not a 
solution containing benzyl alcohol. Solutions reconstituted with 
bacteriostatic water for injection must be used within 7 days. Solutions 
reconstituted with sterile water for injection must be used immediately. 
Parenteral admixture is stable for 24 hours stored at room temperature and 
for 4 days when stored under refrigeration. 
Solution for injection: Prior to dilution, store vials under refrigeration, 
protect from light. 
 
15.44 Administration:  Due to calcium content, do not administer I.V. solutions at a 
rate > 160 mg/minute. Refer to individual protocols for specific administration 
instructions. 
In combination with irinotecan: Leucovorin is compatible with irinotecan via 
Y-site injection.3 
Leucovorin should be administered I.V. push or I.V. infusion over 30 minutes 
following irinotecan liposome  
In combination with fluorouracil: The fluorouracil is usually given after the 
leucovorin infusion. Leucovorin is usually administered by I.V. bolus injection or 
short (10-120 minutes) I.V. infusion, however, in this trial will be given over 30 
minutes. Other administration schedules have been used; refer to the treatment 
section of the protocol for specific directions. 
 
 

 
67  
ACCRU-GI-1603 
 
 
15.45 Pharmacokinetic information: 
Metabolism: Intestinal mucosa and hepatically to 5-methyl-
tetrahydrofolate (5MTHF; active) 
Half-life elimination: ~4-8 hours 
Time to peak: I.V.: Total folates: 10 minutes; 5MTHF: ~1 hour 
Excretion: Urine (primarily); feces 
 
 
15.46 Potential Drug Interactions:   
 
Decreased Effect: May decrease efficacy of 
trimethoprim/sulfamethoxazole against Pneumocystis carinii pneumonia.  
 
15.47 Known potential adverse events: Consult the package insert for the most 
current and complete information. 
 
Frequency not defined:  
Dermatologic: Erythema, pruritis, skin rash, urticarial 
Hematologic & oncologic:  Thrombocytopenia 
Hypersensitivity:  Anaphylactoid reaction, hypersensitivity reaction 
Respiratory:  Wheezing 
 
15.48 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
 

 
68  
ACCRU-GI-1603 
 
 
15.49  Nursing Guidelines 
 
15.491 Headache may occur.  Advise patient that analgesics such as Tylenol 
may help.  Instruct patient to report any headache that is unrelieved. 
 
15.492 Observe for sensitization reaction (rash, hives, pruritis, facial flushing, 
and wheezing).  
 
15.493 May potentiate the toxic effects of fluropyrimidine (5-FU) therapy, 
resulting in increased hematologic and gastrointestinal (diarrhea, 
stomatitis) adverse effects. Monitor closely. 
 
15.494 May cause mild nausea or upset stomach. Administer antiemetics if 
necessary and evaluate for their effectiveness. 
 
15.495 If Leucovorin is being used as rescue for high dose methotrexate, does 
must be given on time. Impress this to the patient. If patient is taking oral 
Leucovorin at home and is unable to take secondary to nausea, instruct 
patient to notify the health care team immediately to arrange for other 
methods of administration.  
 
16.0  
Statistical Considerations and Methodology  
 
16.1 
Overview 
 
This is a phase I/Ib/II study of the nal-IRI/5FU with rucaparib (MRF) combination.  
 
The phase I portion of this study is a 3+3 trial designed to establish the recommended 
dose level of the nal-IRI/5FU with rucaparib combination in patients with pancreatic and 
gastroesophageal cancers (up to 2 lines of prior therapy), colorectal cancer (up to 3 lines 
of prior therapy), and biliary tract cancer (up to 1 line of prior therapy).   
 
The phase Ib portion of this study is designed to assess, in a preliminary fashion, 
antitumor efficacy of the recommended dose level of MFR in patients with metastatic 
disease from pancreatic adenocarcinoma who have received no more than 1 line of prior 
therapy in the metastatic setting. The recommended dose level determined in the phase I 
portion of the trial will be used for the Phase Ib portion.  
   
The phase II portion of this study will use a 2-stage Simon design with interim analysis to 
assess the efficacy of MFR in patients with (untreated) metastatic pancreatic cancer and 
BRCA1, BRCA2, or PALB2 mutation.   The recommended dose level determined in the 
phase I portion of the trial will be used for the Phase II portion.  
 
16.11 Primary Objective and Endpoint 
 
Phase I: the primary objective is to determine the recommended dose level of the 
combination MFT nal-IRI/5FU with rucaparib. The end point to this objective is 
to evaluate the incidence of dose-limiting toxicities (DLT) of nal-IRI/5FU with 
rucaparib. 
 

 
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ACCRU-GI-1603 
 
 
Phase Ib: the primary objective is to evaluate, in a preliminary fashion, antitumor 
efficacy and tolerability of the recommended dose level of MFR in patients with 
metastatic disease from pancreatic adenocarcinoma who have received no more 
than 1 line of prior therapy in the metastatic setting. The endpoint to this 
objective is Disease control (DC) rate which is defined to be RECIST (v 1.1) 
complete response, partial response, or stable disease, for at least 24 weeks from 
initiation of study therapy. The purpose of this Phase Ib expansion is to better 
understand the DC rate and appropriate patient population in order to plan a 
Phase II trial.  
 
Specimens will be collected at baseline in all patients, and at 16 weeks in patients 
with disease control at that time.  
 
A portion of the patients will be selected to have known homologous 
recombination (HR) defects, and approximately 25% of the remaining patients 
are expected to have HR defects. 
 
Phase II: the primary objective is to estimate the proportion of evaluable patients 
who reach CR/PR, per RECIST 1.1, ≤32 weeks after registration. Evaluable is 
defined as patients with HRD encompassing BRCA1, BRCA2, and PALB2 
deleterious mutations (germline and somatic), consented, eligible, and received 
any protocol treatment. The end point to this objective is to evaluate changes in 
size of target lesions according to RECIST 1.1  
 
 
16.12 Sample Size 
 
The phase I portion of this study is expected to require a minimum of 49 patients 
and a maximum of 58 patients including 40 patients who will be accrued into the 
expanded phase Ib cohort (see below).   
 
The phase Ib portion of this trial consists of 2 expansion cohorts of patients 
adenocarcinoma who have received no more than 1 line of prior therapy in the 
metastatic setting. The objective of the phase Ib study is exploratory and 
hypothesis generating in nature. The phase 1b analysis is not powered; thus, no 
sample sizes were derived. We plan to enroll 40 patients to the Phase Ib, 
including 28 patients with either unknown mutation status or non-HRD (known 
wildtype for BRCA1, BRCA2, and PALB2 genes) and 12 patients with known 
HR deficiency (known mutation in either BRCA1, BRCA2, or PALB2 genes) 
with the intent of establishing the efficacy of rucaparib in combination with nal-
IRI. In addition to 12 patients with known HR deficiency due to mutations in 
BRCA1, BRCA2, or PALB2, we expect that 7 of 28 Unknown/Non-HRD cohort 
patients will have HR deficiency since 25% of PDAC patients have defects in 
DNA repair.  
 
The phase II portion of this study is expected to require a minimum of 11 and a 
maximum of 21 untreated pancreatic patients with HRD encompassing BRCA1, 
BRCA2, or PALB2 deleterious mutations (germline and somatic).  An additional 
3 patients with untreated pancreatic cancer and with BRCA1, BRCA2 or PALB2 
deleterious mutation will be accrued to account for ineligibility, cancellation, 
major treatment violation, or other reasons.  We anticipate accruing patients with 

 
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ACCRU-GI-1603 
 
 
other HRD (other than BRCA1, BRCA2, or PALB2) during the phase II portion 
of the trial for exploratory analysis. Therefore, the phase II portion is expected to 
screen 200 patients and accrue 24 patients with HRD encompassing BRCA1, 
BRCA2 and PALB2 patients and another 28 patients with other HRD with an 
overall sample size will be a maximum of 52 patients. 
 
16.13 Accrual Rate and Study Duration 
 
The anticipated accrual rate for Phase I is 1 patient per month. At this rate, it will 
likely take about 4 months to enroll, treat, and evaluate each set of 3 patients in 
the phase I portion of this study. The phase I portion is expected to take between 
12 and 24 months. 
 
The anticipated accrual rate for Phase Ib is 3-4 pancreatic cancer patients per 
month.  The phase Ib portion is expected to take up to 20 months.  
 
The anticipated screening rate for Phase II portion is approximately 8-10 patients 
per month.  The anticipated accrual rate for Phase II is approximately 1-2 patients 
per month for patients with untreated pancreatic cancer with HRD encompassing 
BRCA1, BRCA2 and PALB2 patients. Therefore, the accrual period is expected 
to be between 12 and 24 months, depending upon whether the trial will continue 
accruing patients beyond the interim analysis.  
 
The total study duration is expected to be approximately 24 to 48 months until 
the last patient accrued in the Phase II portion has been observed for at least 4 
months.  
 
16.2 
Phase I portion:  
 
The phase I portion of this trial is a single arm phase I study utilizing cohort-of-3 design 
to determine the recommended dose level of the combination of nal-IRI and 5FU with 
rucaparib (MFR) in patients with metastatic disease from pancreatic cancer (up to 2 lines 
of prior therapy), colorectal cancer (up to 3 lines of prior therapy), gastroesophageal 
cancer (up to 1 line of prior therapy) and biliary tract cancer (BTC; up to 1 line of prior 
therapy allowed).   
 
Decisions regarding the reopening of the cohort to new patients, the expansion of any 
other cohort, and the need to dose reduce patients already receiving treatment at the dose 
level in question will be made by the Study Chair(s). 
 
All patients meeting the eligibility criteria who have signed a consent form and have 
received one dose of MFR will be included in the analysis.  Patients removed from the 
study during cycle 1 for reasons other than toxicity maybe replaced. 
   
16.21 MTD Definition: Maximum Tolerated Dose (MTD) is defined as the dose level 
below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-
third of patients (at least 2 of a maximum of 6 new patients). A total of 6 patients 
treated at the MTD will be sufficient to identify common toxicities at the MTD. 
For instance, those toxicities with an incidence of at least 25% will be observed 
with a probability of at least 82% (1-(1-0.25)6). section 7.42 for DLT definitions.   

 
71  
ACCRU-GI-1603 
 
 
 
16.22    MTD Determination 
 
16.221 The first cohort of three patients will be treated at the starting dose level 
(DL1).  
 
16.222 Three patients will be treated at a given dose level and observed for at 
least 4weeks (Cycle 1) from start of treatment to assess toxicity.  
 
16.223 If DLT is not seen in any of the 3 patients, 3 new patients will be accrued 
and treated at the next higher dose level. If DLT is seen in 2 or 3 of 3 
patients treated at a given dose level, then the next 3 patients will be 
treated at the next lower dose level, if only 3 patients were enrolled and 
treated at this lower dose level.  
 
16.224 If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. If 
DLT is seen in at least one of these additional three patients (≥2 of 6), the 
MTD will have been exceeded, and further accrual will cease to this 
cohort (see 16.223 for further details). If dose-limiting toxicity (DLT) is 
not seen in any of the three additional patients, 3 new patients will be 
accrued and treated at the next higher dose level.  
 
16.225 After enrolling 6 patients on a specific dose level, if DLT is observed in 
at least 2 of 6 patients, then the MTD will have been exceeded and 
defined as the previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will be treated at this 
lower dose level such that a total of 6 patients are treated at the MTD to 
more fully assess the toxicities associated with the MTD. 
 
16.226 Dose de-escalation: If dose-limiting toxicity meets the stopping 
boundaries set by the above dose escalation algorithm at dose level 1   
(for example, more than 1 out of 3 patients or more than 1 out of 6 
patients), the next cohort of three patients will be entered at a dose level 
of -1. Further dose re-escalation will depend on the toxicity profile 
observed at dose level -1, and re-evaluation of the regimen by the study 
team may be done. 
 
16.227 If a patient fails to complete the initial course of therapy (See Section 
13.4) and did not have a DLT while on study, the patient will be regarded 
as uninformative in regard to the primary study goal and an additional 
patient will be treated at the current dose level; however, all toxicity 
information will be utilized in the analysis. 
 
16.228  DL2-A (formerly known as DL1-A) was added as an intermediate dose 
level between DL 1 and DL2-B (formerly known as DL2) (Amendment 
3). Following the approval of Amendment 3, enrollment will re-open to 
DL2-A. If DLTs are seen in less than 2 out of 6 patients treated at DL2-A 
then DL2-A will be considered the MTD. If DLTs are observed in at 

 
72  
ACCRU-GI-1603 
 
 
least 2 patients treated at DL2-A then enrollment will resume at the next 
lowest DL until MTD is met.   
 
 
16.23 Analysis plans: All the relevant results pertaining to toxicity, MTD, laboratory 
correlates will be examined in an exploratory and hypothesis-generating fashion.  
 
16.231 Adverse events profile: The number and severity of all adverse events 
(overall, by dose-level, and by tumor group) will be tabulated and 
summarized in this patient population. The grade 3+ adverse events will 
also be described and summarized in a similar fashion. This will provide 
an indication of the level of tolerance for this treatment combination in 
this patient group  
 
16.232 Toxicity Profile: The term toxicity is defined as adverse events that are 
classified as either possibly, probably, or definitely related to study 
treatment. Non-hematologic toxicities will be evaluated via the ordinal 
CTC standard toxicity grading. Hematologic toxicity measures of 
thrombocytopenia, neutropenia, and leukopenia will be assessed using 
continuous variables as the outcome measures (primarily nadir) as well 
as categorization via CTC standard toxicity grading. Overall toxicity 
incidence as well as toxicity profiles by dose level, patient and tumor site 
will be explored and summarized.  
 
16.233 Response: Objective responses, as defined per RECIST 1.1, will be 
summarized by simple descriptive summary statistics delineating 
complete and partial responses as well as stable and progressive disease.  
 
16.3 
Phase Ib portion 
 
The phase Ib portion of this trial consists of an expansion cohort of patients with 
metastatic disease from pancreatic adenocarcinoma who have received no more than 1 
line of prior therapy in the metastatic setting. Patients will be separated into two cohorts 
based on their HRD status (section 5). 
 
16.31 Analysis plans: All the relevant results pertaining to toxicity, MTD, laboratory 
correlates will be examined in an exploratory and hypothesis-generating fashion. 
 
16.32    Disease control (DC) is defined as achieving CR, PR, or maintaining SD (per 
RECIST v1.1) as the tumor assessment result for at least 24 weeks. Disease 
Control Rate will be estimated by the number of evaluable patients achieving 
disease control divided by the total number of evaluable patients. Evaluable 
patients for the primary endpoint are defined as who have signed the consent 
form, are eligible, received any protocol treatment. Point estimates will be 
generated for disease control rates within each cohort along with 95% binomial 
confidence intervals. (Clopper, C.J and E.S. Pearson, The Use of Confidence or 
Fiducial Limits Illustrated in the Case of Binomial. Biometricka, 1934.26(4).: p. 
404-413).  
  
 

 
73  
ACCRU-GI-1603 
 
 
16.4 
Phase II portion  
 
The phase II portion will include a safety run-in to assess whether there is unacceptable 
toxicity in the first 6 patients accrued (BRCA1/2 and PALB2, and other HRD together) 
without halting the trial. The phase II portion will use a 2-stage Simon design and an 
interim analysis with relaxed probability of stopping for futility to assess the efficacy of 
MFR in patients with untreated pancreatic cancer with BRCA1/2 and PALB2. Patients 
with untreated pancreatic cancer with HRD other than BRCA1/2 and PALB2 will be 
accrued for exploratory analysis. The recommended dose level determined in the phase I 
portion of the trial will be used as the starting dose for Phase II. 
  
16.41  Primary Endpoint 
 
 
 
The primary endpoint for the phase II portion of the trial will be the best response 
rate at 32 weeks, which is defined as the number of patients who had response 
≤32 weeks of registration divided by the number of evaluable patients. Response 
is defined as either complete response (CR) or partial response (PR), per RECIST 
1.1. 
 
16.42 Decision Rule 
 
The largest success proportion (proportion of evaluable patients with CR/PR) 
where the proposed treatment regimen would be considered ineffective in this 
population is 23% (Von Hoff et. al., 201329 and Conroy et. al., 201130), and the 
smallest success proportion that would warrant subsequent studies with the 
proposed regimen in this patient population is 45%.  
 
Evaluable patients for the primary endpoint are defined as patients with HRD 
encompassing BRCA1, BRCA2, and PALB2 deleterious mutations (germline 
and somatic), consented, eligible, and received any protocol treatment.  The 
following two-stage Simon’s design and an interim analysis with relaxed 
probability of stopping for futility uses a minimum of 11 and a maximum of 21 
patients to test the null hypothesis that the true success proportion in a given 
patient population is at most 23%. The current design assumes a one-sided alpha 
level 0.1 and 80% power.  The above power calculation was done using Simon’s 
like design with relaxed futility stopping (Ivanova A.) and assumes a one-sided 
alpha level 0.1, 80% power, and lower and upper bound for the probability of 
stable disease (SD) to be 0.1 and 0.2, respectively. 
 
16.421 STAGE 1 
 
 
 
Among first 11 patients enrolled into study, if 2 or fewer patients with 
CR/PR/SD are observed ≤16 weeks after registration, we will consider 
this regimen ineffective in this patient population and terminate the 
study. Otherwise, if at least 3 patients with CR/PR/SD are observed ≤32 
weeks after registration, we will proceed to Stage 2 and continue accrual.  
 
16.422 STAGE 2 
 
The regimen will be considered ineffective if either enrollment is 

 
74  
ACCRU-GI-1603 
 
 
discontinued after stage 1 or if 7 or fewer patients with CR/PR are 
observed in the first 21 evaluable patients. This regimen will be 
considered promising if 8 or more patients with CR/PR are observed in 
the first 21 evaluable patients.  
 
16.423 Over Accrual 
 
If more than the target number of patients are accrued, the additional 
patients will not be used to evaluate the stopping rule or used in any 
decision-making process. Analyses involving over accrued patients are 
discussed in Section 16.5.  
 
16.424 Operating characteristics 
 
The probability of declaring that this regimen warrants further studies 
(i.e. statistical power) under various success proportions and the 
probability of stopping accrual after the first stage can be tabulated as a 
function of the true success proportion as shown in the following table 
(based on simulation study with 10,000 replicates). 
 
If the true success proportion is … 
0.23 
0.30 
0.35 
0.40 
0.45 
Then the probability of declaring that the 
regimen warrants further study is… 
8.34% 
27.60% 45.43% 65.77% 79.69% 
And the probability of stopping at stage 1 is 
12.12% 9.67% 
5.44% 
1.20% 
0.58% 
 
 
16.43 Phase II Analysis Plan  
 
16.431 Primary Endpoint Analysis - Estimation: The proportion of best response 
≤32 weeks will be estimated by the number of evaluable patients who 
reach CR/PR, per RECIST 1.1, ≤32 weeks since registration divided by 
the total number of evaluable patients. Confidence intervals for the 
proportion will be calculated according to the approach of Duffy and 
Santner (1987).  
 
16.432 Secondary Endpoint Analyses  
 
16.432a Overall survival: Survival time is defined as the time from 
registration to death due to any cause. Patients who fail to return 
for evaluation after beginning therapy will be censored for 
survival on the last day of therapy or date last known to be alive, 
whichever is later The distribution of survival time will be 
estimated using the method of Kaplan-Meier (1958).  
 
16.432b Progression-free survival: Progression-free survival is defined as 
the time from registration to the earliest date documentation of 
disease progression or death due to any cause. Patients who fail 
to return for evaluation after beginning therapy will be censored 
for progression on the last day of therapy or date last known to 
be alive, whichever is later. The distribution of progression-free 

 
75  
ACCRU-GI-1603 
 
 
survival will be estimated using the method of Kaplan-Meier 
(1958). 
 
16.432c Toxicity: As per NCI CTCAE version 4.03, the term toxicity is 
defined as adverse events that are classified as either “possibly,” 
“probably,” or “definitely related” to study treatment. The 
maximum grade for each type of toxicity will be recorded for 
each patient, and frequency tables will be reviewed to determine 
toxicity patterns within patient groups. In addition, we will 
review all adverse event data that is graded as 3, 4, or 5 and 
classified as either “unrelated” or “unlikely to be related” to 
study treatment in the event of an actual relationship developing. 
Adverse events and toxicities will be evaluated using all patients 
who have received any study treatment as well as summarizing 
those who have been included in the efficacy analyses. The 
overall adverse event rates for grade 3 or higher adverse events 
will be compared using Chi-Square or Fisher’s Exact tests 
between the two treatment groups. 
 
 
 

 
76  
ACCRU-GI-1603 
 
 
16.5  
Data & Safety Monitoring  
 
16.51  This study will be monitored by the Mayo Data Safety Monitoring Board 
(DSMB) every 6 months.  Toxicity, efficacy and administrative information for 
this trial will be reviewed by the study team routinely.  
 
16.52  Adverse Event Stopping Rules 
 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study reopening to accrual or (2) at any time during the 
conduct of the trial and in consideration of newly acquired information regarding 
the adverse event profile of the treatment(s) under investigation. The study team 
may choose to suspend accrual because of unexpected adverse event profiles that 
have not crossed the specified rule below. 
 
 
 
16.521 Phase I/Ib Adverse Event Stopping Rule 
 
During the first 2 cycles, 4 of the initial 10 treated patients or 40% or 
more of all patients (i.e., when accrual is greater than 10 patients) have 
experienced a Grade 4+ adverse event at least possibly related to study 
treatment, per NCI Common Terminology Criteria for Adverse Events 
v.5.0, excluding the following:  
• 
Grade 4 neutrophil count decreased lasting ≤7 days  
• 
Grade 4 white blood cell decreased lasting ≤7 days  
• 
Grade 4 platelet count decreased lasting ≤7 days  
• 
Grade 4 diarrhea responding to optimal support 
 
 
 
 
16.522 Phase II Adverse Event Stopping Rules  
 
Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (i.e. 
an adverse event with attribute specified as “possible”, “probable”, or 
“definite”) that satisfy either of the following:  
 
• 
If  1 or more patients out of the first 6 patients (either HRD 
encompassing BRCA1, BRCA2, PALB2 or other HRD) 
experience grade 5 events (death) deemed at least possible 
(possible, probably, or definite) related to MFR, the accrual to 
the study will be suspended to allow for investigation.  After 
consideration by the study team (study chair, statistician) and 
consultation with the sponsor, a decision will be made as to 
whether accrual can be resumed. 
 
• 
If 6 or more patients among the first 20 patients (either HRD 
encompassing BRCA1, BRCA2, PALB2 or other HRD) enrolled 

 
77  
ACCRU-GI-1603 
 
 
or 30% of the patients thereafter develop a grade4+ non-
hematologic toxicities at least possible (possibly, probably or 
definitely) related to treatment, enrollment will be suspended so 
that the adverse event data can be examined and a trial 
recommendation will be formulated an d presented to Mayo 
DSMB. 
 
• 
We note that we will review grade 4 and 5 adverse events 
deemed “unrelated” or “unlikely to be related”, to verify their 
attribution and to monitor the emergence of a previously 
unrecognized treatment-related adverse event. 
 
 

 
78  
ACCRU-GI-1603 
 
 
 
17.0  
Pathology Considerations/Tissue Biospecimens  
 
17.1 
Tissue Biospecimen Submission  
 
17.11 Summary Table of Tissue Biospecimens for This Protocol 
 
Type of tissue 
biospecimen to 
submit 
Mandatory 
or optional 
When to submit 
Reason for 
submission 
(background/
methodology 
section) 
Where to 
find specific 
details for  
biospecimen 
submission 
Formalin-fixed 
paraffin-
embedded 
(FFPE) tissue 
blocks with 
corresponding 
H&E (OR total 
of 10  unstained 
(5) micron slides 
with 
corresponding 
H&E) 
Mandatory 
≤60 days after 
registration 
Correlative 
studies 
(Section 17.3) 
Section 17.2 
*If an institution is not able to provide the tissue, it does not cause the patient to be 
ineligible; however the collection of these tissues is strongly recommended. 
 
 
17.2 
Paraffin Embedded Tissue Blocks/Slides (mandatory for research tissue)  
 
17.21 Submit one formalin fixed paraffin-embedded (FFPE) tumor tissue block from 
the original and/or recurrent surgery with largest amount of invasive tumor (at 
least 1 cm of tumor for cases of surgical resection).   
 
17.22 The FFPE tissue block is preferred; however, if an institution is unable to provide 
a tissue block, cut 10 five-micron unstained slides with corresponding H&E and 
mount on charged glass slides. Label the slides with the ACCRU patient ID 
number, accession number, and order of sections (i.e., 1-10). H&E stain the first 
cut slide (i.e., slide labeled 1). For samples containing less than 7 square 
millimeters of tumor tissue, multiple sections should be mounted onto each slide 
to ensure that the appropriate amount of tumor tissue is available. Ideally, each 
slide must have a minimum of 75% tumor tissue on the slide to be deemed 
adequate for study. Do not bake or place cover slips on the slides.  Please do 
NOT use sticky labels on slides. 
 
17.23 The following materials below are mandatory (unless indicated otherwise) and 
required for shipment: 
 

 
79  
ACCRU-GI-1603 
 
 
• Paraffin embedded tissue blocks with corresponding H&E slide (OR 10 
unstained slides with corresponding H&E(s), per instructions in Section 
17.22).  
• Specimen Submission: Tissue Baseline form 
• Surgical Pathology Report 
• Operative Report (optional) 
 
Note: Please make sure each slide is labeled with the specimen surgical 
pathology number, block number and order of sections cut either via your 
institution’s standard method for labeling or using a permanent marker.  
Labeling with sticky labels is not acceptable. 
 
17.24 The block/slides must be appropriately packed to prevent damage (e.g., slides 
should be placed in appropriate slide container) and placed in an individual 
plastic bag.  Label the bag with the protocol number, ACCRU patient ID number, 
and patient initials. During warm weather months, paraffin blocks should be 
shipped using a refrigerant pack to avoid heat that may melt paraffin and damage 
blocks. 
 
17.25  Tissue specimens must be shipped ≤60 days after registration. 
 
17.26 Verify that the appropriate sections of the Specimen Submission: Tissue Baseline 
form are completed and filled in correctly. Enter information from the Specimen 
Submission: Tissue Baseline form into the remote data entry system on the same 
day the specimen is submitted (see CRF Packet). 
 
17.27 Ship all block/slide tissue specimens and accompanying materials to the ACCRU 
Research Base: 
 
 
 
 
 
17.28 When an appropriate request is submitted, the ACCRU Operations Office will 
forward the block/slides to the ACCRU Research Base Pathology Research Core, 
Mayo Clinic Rochester for processing. 
 
17.29 Frozen Tumor tissue: (None) 
 
17.3 
Study Methodology and Storage Information 
 
17.31 Submitted tissue samples will be analyzed as follows:  
 
Tissue from biopsies will be processed at a Clovis 3rd party diagnostic 
collaborator to obtain comprehensive genomic profiling (CGP) using 
hybridization capture of all coding exons of >300 cancer-related genes and 31 
genes commonly rearranged in cancer. To this end ≥50ng of DNA will be 
extracted from FFPE specimens. All tumors will be sequenced to high (average 

 
80  
ACCRU-GI-1603 
 
 
>570X), uniform coverage. Genomic alterations (base substitutions, small indels, 
rearrangements and copy number alterations) will be determined in tissue from 
tumor biopsies.  
 
 
We will test whether HRD in tumor samples is associated with clinical outcome 
including the following (among others): response to therapy, progression-free 
survival, and overall survival. 
 
17.32 At the completion of the study, any unused/remaining material will be stored in 
the ACCRU Central Operations Office (Attn.: Pathology Coordinator) for future 
research according to the patient consent permission (see Section 6.15).  Potential 
future research may include immunohistochemistry (IHC) analyses to analyze 
predictive biomarkers, changes in expression pattern with therapy, and 
correlation with response and/or adverse events.  When a protocol is developed, 
it will be presented for IRB review and approval. 
 
17.33 Banking of tumor tissue, according to the patient consent permission (see Section 
6.32), is for future research.  As protocols are developed, they will be presented  
 
for ACCRU and IRB review and approval.  (This collection is part of a general 
strategy of investigation for ACCRU studies). 
 
17.34 The institutional pathologist will be notified by the Pathology Coordinator if the 
block may be depleted. 
 
17.35 Blocks requested to accommodate individual patient management will be 
returned promptly upon request. 
 
17.4 
Return of Genetic Testing Research Results   
 
Because the results generated by the genetic testing included in this section are not 
currently anticipated to have clinical relevance to the patient or their family members, the 
genetic results will not be disclosed to the patients or their physicians. 
 
If, at any time, genetic results are obtained that may have clinical relevance, IRB review 
and approval will be sought regarding the most appropriate manner of disclosure and 
whether or not validation in a CLIA certified setting will be required. Sharing of research 
data with individual patients should only occur when data have been validated by 
multiple studies and testing has been done in CLIA-approved laboratories. 
 
 
18.0 
Records and Data Collection Procedures 
 
The RAVE system will be used to collect data. Access the RAVE system through the iMedidata 
portal at 
All data must be entered by Remote Date Entry (RDE) and 
completed by qualified and authorized personnel. All data on the CRF must reflect the 
corresponding source document. Please refer to the ACCRU website for instructions 
 
 
 

 
81  
ACCRU-GI-1603 
 
 
18.1 Submission Timetables 
 
Pre-Registration Material(s) – Phase II Only 
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
Screening (Phase II only) 
Complete only if patient is NOT registered after he/she is pre-
registered 
 
 
Initial Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Institutional Contacts 
 
 
 
 
≤2 weeks  after registration 
Phase of Study 
On-Study  
On-Study: Pancreatic Cancer2  
On-Study: Gastroesophageal Cancer2 
On-Study: Colorectal Cancer2  
On-Study: Biliary Tract Cancer2  
On-Study: Prior Surgery2 
On-Study: Prior Radiation2 
On-Study: Prior Neoadjuvant, Adjuvant or 
Metastatic Therapies2 
Laboratory Tests & Results: Baseline 
Adverse Events: Baseline  
RECIST Measurements: Baseline  
Supporting Documentation: Baseline1 
Specimen Submission: Blood Baseline (see 
Section 14.0) 
Specimen Submission: Tissue Baseline (see 
Section 17.0) 
Patient Status: Baseline 
OP and Path Reports (see Section 17.0)1 
Off Treatment2 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
ACCRU Deviation Form2 
Submit only if applicable during all phases of the study  
(initial, active and observation) 
1.  Upload Op, Path Reports, and tumor molecular profiling report (if available) via the Supporting 
Documentation: Baseline form. This is in addition to the pathology material requirements for tissue 
submission (Section 17.0). 
2. Submit only if applicable. 
 
 
 

 
82  
ACCRU-GI-1603 
 
 
Test Schedule Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
Observation 
Treatment (Intervention)  
X 
X 
 
Treatment (Intervention): Dose 
Modifications, Omissions and Delays2 
X 
 
 
Adverse Events: Solicited 
X 
X 
 
Adverse Events: Other2 
X 
X 
 
Dose Limiting Toxicities (Phase I only) 2 
X 
 
 
RECIST Measurements1  
X 
X 
X 
Supporting Documentation1 
X 
X 
X 
Day 1 Laboratory Tests and Results3 
X 
 
 
Day 15 Laboratory Tests and Results4 
X 
 
 
Specimen Submission: Blood  
X (see Section 14.0) 
 
 
Patient Status: Treatment (Intervention) 
X  
X 
 
Notice of New Primary2 
X 
X 
X 
Consent Withdrawal (choose appropriate 
form) 3 
• Consent Withdrawal: Specimen Only 
• Consent Withdrawal:  Clinical Follow-
Up Only 
• Consent Withdrawal: All Follow-Up 
X 
X 
X 
Off Treatment 
 
X 
 
Lost to Follow-up2 
X 
X 
X 
ACCRU Deviation Form2 
X 
X 
X 
1. Prior to 3rd and subsequent odd cycles (until PD). Upload a copy of documentation of progression in 
RAVE on the Supporting Documentation Form. 
2. Submit only if applicable. 
3. Day 1 of each cycle, beginning with Cycle 1 (until PD). 
4. Day 15 of each cycle, beginning with Cycle 1 (until PD). 
 
 
 

 
83  
ACCRU-GI-1603 
 
 
Follow-up Material(s)  
 
CRF 
Event Monitoring Phase1 
 
q. 6 
months 
until PD2 
 
 
 
At PD2 
After 
PD       
q. 6 
mos. 
 
 
 
Death 
 
 
 
At Each Event 
Occurrence 
Patient Status: Survival and Disease Status 
Follow-Up/Event Monitoring  
X2 
X2 
X 
X 
 
Adverse Events: Late3 
 
 
 
 
X 
Notice of New Primary3 
 
 
 
 
X 
Consent Withdrawal (choose appropriate 
form) 3 
• Consent Withdrawal: Specimen Only 
• Consent Withdrawal:  Clinical Follow-
Up Only 
• Consent Withdrawal: All Follow-Up 
 
 
 
 
X 
Lost to Follow-Up3 
 
 
 
 
X 
ACCRU Deviation Form3 
X3 
X3 
X3 
X3 
 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. Upload a copy of documentation of progression in RAVE on the Supporting Documentation Form. 
3.  Submit only if applicable. 
 
 
19.0  
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies, to determine which items are standard of care and which are 
research at their site.  Refer to the payment synopsis for funding provided per accrual for 
covering study costs, as well as any additional invoiceables that may be allowed. 
 
 
19.2 
Tests to be research funded: 
 
 
 
19.21 Mandatory archival tissue collection  
 
 
 
19.22 cfDNA 
 
 
19.3 
Other budget concerns: 
 
19.31 Clovis will provide rucaparib free of charge to patients while they are 
participating in this study. 
 
19.32 Ipsen will provide irinotecan liposome free of charge to patients while they are 
participating in this study. 
 
 
 

 
84  
ACCRU-GI-1603 
 
 
20.0 
References 
 
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2. 
Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-
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3. 
Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. N Engl J Med 364:1817-25, 2011 
 
4. 
Rahib L, Smith BD, Aizenberg R, et al: Projecting cancer incidence and deaths to 2030: 
the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer 
Res 74:2913-21, 2014 
 
5. 
Witkiewicz AK, McMillan EA, Balaji U, et al: Whole-exome sequencing of pancreatic 
cancer defines genetic diversity and therapeutic targets. Nature communications 6:6744, 
2015 
 
6. 
Grant RC, Selander I, Connor AA, et al: Prevalence of germline mutations in cancer 
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7. 
Waddell N, Pajic M, Patch AM, et al: Whole genomes redefine the mutational landscape 
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8. 
Turner N, Tutt A, Ashworth A: Hallmarks of 'BRCAness' in sporadic cancers. Nature 
reviews. Cancer 4:814-9, 2004 
 
9. 
O'Sullivan CC, Moon DH, Kohn EC, et al: Beyond Breast and Ovarian Cancers: PARP 
Inhibitors for BRCA Mutation-Associated and BRCA-Like Solid Tumors. Frontiers in 
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10. 
Kaufman B, Shapira-Frommer R, Schmutzler RK, et al: Olaparib monotherapy in patients 
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official journal of the American Society of Clinical Oncology 33:244-50, 2015 
 
11. 
Coleman RL, Sill MW, Bell-McGuinn K, et al: A phase II evaluation of the potent, 
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12. 
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ACCRU-GI-1603 
 
 
14. 
Wang-Gillam A, Li CP, Bodoky G, et al: Nanoliposomal irinotecan with fluorouracil and 
folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy 
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15. 
Patricia M.Lorusso, Sara M.Tolaney, Shukmei Wong, et al: Combination of the PARP 
inhibitor veliparib (ABT888) with irinotecan (CPT-11) in patients with triple negative 
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16. 
Ute Hoch, Deborah Charych, al. e: Combining the long-acting topoisomerase 1-inhibitor 
etirinotecan pegol with the PARP inhibitor rucaparib to provide anti-tumor synergy 
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17. 
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18. 
Iain A.McNeish, Amit M.Oza, Robert CC, et al: Results of ARIEL2: A Phase 2 trial to 
prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor 
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19. 
Carnevale J, Ashworth A: Assessing the Significance of BRCA1 and BRCA2 Mutations 
in Pancreatic Cancer. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 33:3080-1, 2015 
 
20. 
Alexandrov LB, Nik-Zainal S, Siu HC, et al: A mutational signature in gastric cancer 
suggests therapeutic strategies. Nature communications 6:8683, 2015 
 
21. 
Chen EX, Jonker DJ, Siu LL, et al: A Phase I study of olaparib and irinotecan in patients 
with colorectal cancer: Canadian Cancer Trials Group IND 187. Investigational new 
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22. 
Talia Golan, Maria Raitses-gurevic, Kelley RK: Overall survival and clinical 
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Duffy, D., and T. Santner (1987). "Confidence intervals for a binomial parameter based 
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24. 
Eisenhauer EA, Therasse P, Bogaert J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
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RECIST guideline (version 1.1).  Eur J Cancer 45(2):  228-247, 2009. 
 
25. 
Ivanova A and Deal A. (2016). Two-stage design for phase II oncology trials with 
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26. 
Ivanova A. Simon’s like design with relaxed futility stopping. 
http://cancer.unc.edu/biostatistics/program/ivanova/SimonsDesignWithRelaxedFutilitySt
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27. 
Kaplan, E. and P. Meier (1958). "Nonparametric estimation from incomplete 
observations." Journal of the American Statistical Association 53: 457-448. 
 
28. 
Mateo J, Carreira S, Sandhu S, Miranda S, et. al. DNA-Repair Defects and Olaparib in 
Metastatic Prostate Cancer.  N Engl J Med. 2015 Oct 29;373:1697-708. 
 
29. 
Von Hoff DD1, Ervin T, Arena FP, et. al. Increased survival in pancreatic cancer with 
nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369:1691-703. 
 
30. 
Conroy T, Desseigne F, Ychou M, et. al. FOLFIRINOX versus gemcitabine for 
metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364:1817-25. 
 
31. 
Clopper, C.J. and E.S. Pearson, The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika, 1934. 26(4): p. 404-413. 
 
 
 

ACCRU-GI-1603 
Appendix IA 
 
Phase I 
 
ACCRU Informed Consent Template  
for Cancer Treatment Trials 
(English Language) 
 
*NOTES FOR LOCAL INVESTIGATORS: [NOTE: Retain this section and asterisk item below for 
ACCRU model consents] 
• The goal of the informed consent process is to provide people with sufficient information for 
making informed choices.   The informed consent form provides a summary of the clinical study 
and the individual's rights as a research participant.  It serves as a starting point for the necessary 
exchange of information between the investigator and potential research participant.   
• A blank line, __________, indicates that the local investigator should provide the appropriate 
information before the document is reviewed with the prospective research participant.  
• Suggestion for Local Investigators:  The NCI web site has information explaining clinical trials.  
The web page is entitled: "Taking Part in Cancer Treatment Research Studies."  A free PDF may 
be downloaded from the NCI web site:  
 
• Optional feature for Local Investigators: Reference and attach drug sheets, pharmaceutical 
information for the public, or other material on risks.  Check with your local IRB regarding review 
of additional materials. 
 
*These notes for {authors and} investigators are instructional and should not be included in the informed 
consent form given to the prospective research participant.  
 

ACCRU-GI-1603 
Appendix IA 
Page 1 of 17 
Phase I 
 
 
ACCRU-GI-1603, Phase I Study of Irinotecan Liposome (nal-IRI), 
Fluorouracil, Leucovorin and Rucaparib in the Treatment of Select 
Gastrointestinal Metastatic Malignancies Followed by a Phase Ib of First 
and Second Line Treatment of both Unselected and Selected (for BRCA ½ 
and PALB2 Mutations) Patients with Metastatic Adenocarcinoma of the 
Pancreas then Followed by a Phase II Study of First Line Treatment of 
Selected Patients with Metastatic Adenocarcinoma of the Pancreas with 
Genomic Markers (Signature) of Homologous Recombination Deficiency 
(HRD) 
 
This is an important form.  Please read it carefully.  It tells you what you need to know about this 
research study.  If you agree to take part in this study, you need to sign this form.  Your signature 
means that you have been told about the study and what the risks are.  Your signature on this form also 
means that you want to take part in this study. 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to you.   
Clinical trials include only people who choose to take part. Please take your time to make your decision 
about taking part.  You may discuss your decision with your friends and family.  You can also discuss it 
with your health care team.  If you have any questions, you can ask your study doctor for more 
explanation.  
 
You are being asked to take part in this research study because you have cancer of the pancreas, 
colorectal, gastroesophageal, or biliary tract. 
 
NOTE: If you have advanced colorectal cancer and have not received standard treatment with FOLFOX 
or FOLFIRI prior to entering the study, please note that FOLFOX and FOLFIRI have proved to provide 
more benefit than receiving 5FU alone.  
 
Why is this research study being done? 
 
This study is being done in three parts:  Phase I, Phase 1b and Phase II. You are being asked to take part 
in the Phase I portion of the study because you have pancreatic, colorectal, gastroesophageal or biliary tract 
cancer. The purpose of this Phase I research study is to find the highest dose of nal-IRI and rucaparib that 
can safely be given in combination with 5-FU and leucovorin to patients who have colorectal, pancreatic, 
gastroesophageal or biliary tract cancer without causing bad side effects. 
 
How many people will take part in the research study? 
 
About 9 people will take part in the Phase I study.   
 
At the beginning of the study, 3 patients will be treated with a low dose of the drugs.  If this dose does not 
cause bad side effects, it will slowly be made higher as new patients take part in the study.  A total of 9 
patients are the most that will be able to enter the Phase I part of this study. 
 

ACCRU-GI-1603 
Appendix IA 
Page 2 of 17 
Phase I 
 
 
 
What will happen if I take part in this research study? 
 
Before you begin the study …  
 
Within 1 to 3 weeks before study registration – You will need to have the following exams, tests or 
procedures to find out if you can be in the study.  These exams, tests or procedures are part of regular 
cancer care and may be done even if you do not join the study.  If you have had some of them recently, 
they may not need to be repeated.  This will be up to your study doctor. 
 
• Medical history and physical exam; your doctor will also ask how well you perform activities in 
your daily life. 
• A check to see if any of the side effects that may be caused by the study drugs are already 
present. 
• Routine blood tests – equal to about the amount in 2 tablespoons will be taken from a vein in 
your arm. 
• Research blood tests – when you have the routine blood test done, we will also take between 2 
teaspoons and 4 tablespoons of additional blood for research and banking for future research.  
Giving this extra blood is required if you participate in this study. 
• CT scan or MRI to measure your tumor  
• Electrocardiogram (ECG) to look at your heart and heart valves to see how well they are 
working. 
• A pregnancy test done by taking a blood sample from a vein in your arm within 21 days of 
being registered on the study, and again within 7 days of being registered – if you are a woman 
of childbearing potential. The pregnancy test results must be negative in order for you to 
continue on the study. 
• Collection of a tumor sample from your previous surgery or biopsy for research purposes; no 
additional tumor tissue will be taken from you during this study.  
• This sample will be used to look for genes in your tumor that will predict the effectiveness of 
the study drugs in future patients with pancreatic, colorectal, gastroesophageal or biliary tract 
cancer.  
 
During the study …  
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures.  They are part of regular cancer care.  
 
• Medical history and physical exam; your doctor will also ask how well you perform activities in 
your daily life and review your Patient Medication Diary.. 
• A check to see if any of the side effects that may be caused by the study drugs are already 
present. 
• Routine blood tests – equal to about the amount in 2 tablespoons will be taken from a vein in 
your arm. 
• CT scan or MRI to measure your tumor  
• A pregnancy test done by taking a blood sample from a vein in your arm every 28 days before 
each treatment (if you are a woman of childbearing potential). The pregnancy test results must 
be negative in order for you to continue on the study. 

ACCRU-GI-1603 
Appendix IA 
Page 3 of 17 
Phase I 
 
 
 
You will need the following tests and procedures that are part of regular cancer care.   They are being 
done more often because you are in this study.   
 
• A pregnancy test done by taking a blood sample from a vein in your arm every 28 days before 
each treatment (if you are a woman of childbearing potential). The pregnancy test results must 
be negative in order for you to continue on the study. 
 
You will need these tests and procedures that are either being tested in this study or being done to 
see how the study is affecting your body. 
 
• Research blood tests – when you have the routine blood test done, we will also take between 2 
teaspoons and 4 tablespoons of additional blood for research and banking for future research.  
Giving this extra blood is required if you participate in this study. 
 
This research will explore possible genetic or inherited reasons for how patients respond to medications. 
Your blood and tissue samples contain genes, which are made up of DNA and proteins that serve as the 
"instruction book" for the cells that make up our bodies. Your samples will help us study how genes 
interact with other factors to influence the development and treatment of diseases. Because the genetic 
tests in this study are not used for regular medical care, you will not be told the results of the test(s), and 
the test results will not be put in your medical record. 
 
There is more information about these research tests at the end of this form. 
 
Once it is determined that you are eligible for the study and agree to take part, you will begin treatment. 
Treatment takes place over several 28-day periods; each 28-day period is called a cycle.  
 
For the first 28-day cycle, treatment includes the following… 
 
On days 1 and 15 of every 28-day cycle, about 30-60 minutes before receiving the study drugs noted 
below, you will be given medications (dexamethasone (or similar) and ondansetron (or similar)) 
through a needle placed in your arm (also referred to as an IV (intravenous)) to make side effects 
less serious and less uncomfortable. These medications are sometimes known as pretreatment 
medications. 
 
On days 1 and 15, after receiving the pretreatment medications, you will receive nal-IRI (50mg), 
5-FU (2400mg) and leucovorin (400mg). These drugs will be given to you through the IV.   
 
In addition to the IV study drugs, you will also take the study drug, rucaparib (400mg), in pill form, 
by mouth, two times every day beginning on day 4 of the first week, and continue through day 13. 
You will not take this drug on days 14-17. On day 18 you will start taking rucaparib again, and 
continue taking through day 27, then stop taking this drug again on day 28 (see study calendar 
below).   
 
For the second 28-day cycle, the dose of nal-IRI will be increased to 70 mg, and treatment includes 
the following… 
 
On days 1 and 15 of every 28-day cycle, you will receive nal-IRI (70mg), 5-FU (2400mg) and 
leucovorin (400mg). These drugs will be given to you through a needle placed in your arm (also 

ACCRU-GI-1603 
Appendix IA 
Page 4 of 17 
Phase I 
 
 
referred to as an IV (intravenous)).  You will be given some medications 30-60 minutes before 
you receive the IV study drugs to lessen the side effects of the chemotherapy.  
 
Before receiving the above-mentioned study drugs, you will be given medications (dexamethasone 
(or similar) and ondansetron (or similar)) through the IV to make side effects less serious and less 
uncomfortable. 
 
In addition to the IV study drugs, you will also take the study drug, rucaparib (400mg), in pill form, 
by mouth, two times every day beginning on day 4 of the first week, and continue through day 13. 
You will not take this drug on days 14-17. On day 18 you will start taking rucaparib again, and 
continue taking through day 27, then stop taking this drug again on day 28 (see study calendar 
below).   
 
For the third 28-day cycle, the dose of rucaparib will be increased to 600 mg, and treatment 
includes the following… 
 
On days 1 and 15 of every 28-day cycle, you will receive nal-IRI (70mg), 5-FU (2400mg) and 
leucovorin (400mg). These drugs will be given to you through a needle placed in your arm (also 
referred to as an IV (intravenous)).  You will be given some medications 30-60 minutes before 
you receive the IV study drugs to lessen the side effects of the chemotherapy.  
 
Before receiving the above-mentioned study drugs, you will be given medications (dexamethasone 
(or similar) and ondansetron (or similar)) through the IV to make side effects less serious and less 
uncomfortable. 
 
In addition to the IV study drugs, you will also take the study drug, rucaparib (600mg), in pill form, 
by mouth, two times every day beginning on day 4 of the first week, and continue through day 13. 
You will not take this drug on days 14-17. On day 18 you will start taking rucaparib again, and 
continue taking through day 27, then stop taking this drug again on day 28 (see study calendar 
below).  
 
If, you have side effects that get too bad at any time during these cycles, the doses listed above will be 
decreased until the side effects get better. Treatment may discontinue completely if side effects are too 
bad or your cancer gets worse. 
 
 
Medication Diary 
 
You will be asked to keep a daily record (Patient Medication Diary) of when you take the study 
medication, rucabarib, and every day write down the day and time you take the medication. If you notice 
any side effects, you can include this information in the Comments section of the diary. 
 
 
 

ACCRU-GI-1603 
Appendix IA 
Page 5 of 17 
Phase I 
 
 
Study Calendar 
 
You will receive nanoliposomal irinotecan (nal-IRI) + leucovorin + fluorouracil (5-FU) + rucaparib as 
outlined in the calendar below over a 28-day period. This 28-day period of time is called a cycle.  The cycle 
will be repeated 3 times.  Each cycle is numbered in order.  The chart below shows what will happen to you 
during Cycle 1 and future treatment cycles as explained previously.  The left-hand column shows the day in 
the cycle and the right-hand column tells you what to do on that day. 
 
Day  
 
What you do 
Up to 21 days 
before starting 
treatment 
• Medical history and physical exam; your doctor will also ask how well you 
perform activities in your daily life. 
• A check to see if any of the side effects that may be caused by the study 
drugs are already present. 
• Routine blood tests  
• CT scan or MRI  
• Electrocardiogram (ECG)  
• Mandatory submission of a tumor sample from your previous surgery or 
biopsy  
Up to 7 days 
before starting 
treatment 
• Pregnancy test (only if you are a woman of childbearing potential) 
• Mandatory research blood tests  
Day 1 of each 
cycle 
• Prior to dosing - Pregnancy test (only if you are a woman of childbearing 
potential) 
• Medical history and physical exam; your doctor will also ask how well you 
perform activities in your daily life. 
• A check to see if you are having any side effects from study drugs. 
• Review Patient Medication Diary 
• Routine blood tests  
• ECG 
• Receive pretreatment medications through an IV.  
• Receive nal-IRI, 5-FU and leucovorin through an IV.   
Days  4-13 
• Take rucaparib, in pill form, by mouth, two times every day beginning on 
day 4 of the first week, and continue through day 13. 
Days 14-17 
• Stop taking rucaparib. 
Day 15 
• Medical history and physical exam; your doctor will also ask how well you 
perform activities in your daily life. 
• A check to see if you are having any side effects from study drugs. 
• Routine blood tests  
• Receive pretreatment medications through an IV.  
Receive nal-IRI (50mg), 5-FU (2400mg) and leucovorin (200mg) through an 
IV.   
Days 18-27 
• Take rucaparib, in pill form, by mouth, two times every day beginning on 
day 18 and continue through day 27. 
Days 22 – 28 
• On one of these days (Day 22 – 28) before every odd-numbered cycle (i.e., 
before cycle 3 or cycle 5, etc.), do the following: 
 CT scan or MRI to measure your tumor  
 Routine blood tests 

ACCRU-GI-1603 
Appendix IA 
Page 6 of 17 
Phase I 
 
 
 
 
 
 
 
 
Study Calendar – Continued 
 
 Day 
 
What you do 
Day 28 
• Stop taking rucaparib. 
Cycle 2 
• Repeat Days 1-28 as above 
Cycle 3 
• Repeat Days 1-28 as above 
End of 
Treatment (after 
you complete the 
full treatment, or 
if your disease 
progresses or 
you stop the 
treatment for any 
reason) 
• Medical history and physical exam; your doctor will also ask how well you 
perform activities in your daily life. 
• A check to see if you are having any side effects from study drugs. 
• Review Patient Medication Diary 
• Routine blood tests 
• Mandatory  research blood tests 
• CT scan or MRI 
 
When you are finished taking the study drugs… 
 
Within about 30 days after your last treatment, the following tests and procedures will be done:  
 
• Medical history and physical exam; your doctor will also ask how well you perform activities in 
your daily life and review your Patient Medication Diary. 
• A check to see if you are having any side effects from study drugs. 
• Routine blood tests – equal to about the amount in 2 tablespoons will be taken from a vein in 
your arm. 
• Research blood tests – when you have the routine blood test done, we will also take between 2 
teaspoons and 4 tablespoons of additional blood for research and banking for future research.   
 
 
How long will you be in the research study? 
 
For the Phase I part of this study, you will be asked to take nal-IRI, 5-FU, leucovorin and rucaparib for 
about 3 months or until your disease gets worse, or you have side effects that you are unable to tolerate.   
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your 
best interest; if you do not follow the study rules; or if the study is stopped. 
 
After you are finished taking the study drugs, the study doctor will ask you to visit the office for periodic 
follow-up exams for about 3 years. 
 
Can I stop being in the research study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop safely.  
 

ACCRU-GI-1603 
Appendix IA 
Page 7 of 17 
Phase I 
 
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the nal-IRI, 5-
FU, leucovorin and rucaparib can be evaluated by your doctor.  Another reason to tell your doctor that 
you are thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you. 
 
What side effects or risks can I expect from being in the research study? 
 
If you have not previously received standard treatments for your cancer and decide to take part in this 
research study, you are declining standard treatment and the potential benefits of these standard 
treatments. 
 
You may have side effects while on the study.  Everyone taking part in the study will be watched carefully 
for any side effects.  However, doctors don’t know all the side effects that may happen.  Side effects may 
be mild or very serious.  Your health care team may give you medicines to help lessen side effects.  Many 
side effects go away soon after you stop taking the combination of nal-IRI + 5-FU + leucovorin + rucaparib.  
In some cases, side effects can be serious, long lasting, or may never go away. There also is a risk of 
death. 
 
You should talk to your study doctor about any side effects that you have while taking part in the study.    
 
Risks and side effects related to rucaparib: 
 
Oral rucaparib is an experimental drug that may have side effects that cannot be predicted at this time.    
Rare or unknown side effects could possibly occur, including life-threatening reactions.   
Common Side Effects of Rucaparib 
The following is a list of the most commonly-reported side effects reported by patients who have received 
rucaparib, whether taking rucaparib alone or at the same time they were receiving chemotherapy: 
• Low blood counts (especially of the white blood cells, but sometimes of red blood cells and 
platelets).  Sometimes fever occurs with the low blood counts   
o A low white blood cell count puts you at higher risk for infection.  If you have a 
temperature higher than 100.4°F (38.0°C) at any time during the study, you must tell the 
study doctor immediately.   
o A low red blood cell count may make you feel tired or dizzy.  If you feel dizzy while 
taking rucaparib, you should avoid potentially hazardous tasks such as driving or operating 
machinery. 
o A low platelet count affects the ability of your blood to clot and could lead to bleeding 
events 
• Stomach-related effects such as nausea, vomiting, diarrhea, loss of appetite, heartburn, and 
constipation 
• Feeling tired (Fatigue) 
• Headache 
• Abdominal pain 
• Elevated liver enzymes 
• Dizziness 
• Bad taste in mouth  (or altered sense of taste) 

ACCRU-GI-1603 
Appendix IA 
Page 8 of 17 
Phase I 
 
 
• Increased sensitivity to sunlight- please use appropriate sun protection  
• Increased serum creatinine 
• Increase in cholesterol 
• Rash  
• Pruritis (itchy skin) 
• Dyspnea (difficult or labored breathing)  
• Due to the risk of permanent damage or death to a developing embryo/fetus, both women of 
childbearing potential and men and their opposite sex partners of reproductive potential should use 
contraception during dosing and for 6 months after completing treatment with rucaparib. 
 
Rare Side Effects (less than 1% of patients)  
 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been reported in a very small 
number of patients treated with rucaparib. MDS is a pre-cancerous condition where the bone marrow is 
not as good at producing blood cells (red and/or white blood cells and/or platelets) as it was before. 
People with MDS need transfusions (red blood cells and/or platelets) and/or other treatments. In some 
cases MDS will progress to AML, which is a cancer of the bone marrow where more abnormal and 
immature white blood cells (also called blasts) are made than normal white blood cells. People with AML 
need treatment with chemotherapy and/or a transplant. Patients may develop AML without first being 
diagnosed with MDS. MDS/AML can be fatal and led to death in 2 patients on rucaparib (0.5%). 
 
Events of MDS and AML have also been reported with PARP inhibitors similar to rucaparib. At this time 
it is not known whether PARP inhibitors cause MDS or AML or if these developed as a result of previous 
chemotherapy these patients received. Your Study Doctor will closely monitor your blood cell levels 
during treatment. If he/she has any concerns about your blood counts you may be asked to have a biopsy 
of your bone marrow. 
 
If you develop low blood counts, or if you have any other significant side effects, you may need to stop 
taking rucaparib until you recover from these side effects.  The study doctor may also decide to lower 
your dose of rucaparib if you experience certain side effects.  
 
 
Allergic Reactions 
As with any drug, it is possible that you could have allergic reactions to rucaparib, such as itching, skin 
rash, facial swelling, and/or a severe or sudden drop in blood pressure.  A sudden drop in blood pressure 
could lead to shock with loss of consciousness and/or possible seizures, including the possibility of death.  
If you have any of the above symptoms, seek medical attention right away. 
 
Risks and side effects related to nal-IRI + 5-FU + leucovorin include those which are: 
 
Likely (more than 10%) 
 
In a clinical trial evaluating the effectiveness of nal-IRI in the treatment of metastatic pancreatic cancer, 
117 patients received nal-IRI in combination with 5-FU and leucovorin. In this group of patients, the most 

ACCRU-GI-1603 
Appendix IA 
Page 9 of 17 
Phase I 
 
 
common side effects that happened in at least 12 of the 117 patients (more than 10% of those patients) 
included the following: 
 
• Diarrhea 
• Vomiting 
• Nausea 
• Decreased appetite 
• Fatigue (tiredness) 
• Anemia (decreased red blood cells or hemoglobin, which may cause tiredness and lack of energy) 
• Fever 
• Neutropenia (decrease in a type of white blood cells called neutrophils, may increase the risks of 
infections) 
• Abdominal pain 
• Constipation 
• Asthenia (lack of energy) 
• Weight loss 
• Leukopenia (decrease in white blood cells) 
• Hair loss (alopecia) 
• Stomatitis (inflammation of the lining of the mouth) 
• Back pain 
• Dizziness 
• Hypokalemia (decrease in blood potassium levels) 
• Peripheral edema (collection of fluid in the tissues of the body) 
• Mucosal inflammation (lining of mouth, esophagus, stomach and intestines) 
• Thrombocytopenia (a decrease in platelets (particles that help the blood to clot, may cause 
bruising or bleeding) 
 
Less Likely (between 5% and 10% of patients) 
 
The less commonly seen side effects that occurred in at least 6 of the 117 patients (more than 5% of those 
patients) were: 
 
• Upper abdominal pain 
• Dehydration 
• Hypomagnesemia (decrease in blood magnesium levels) 
• Hypoalbuminemia (decrease in a type of blood protein called albumin) 
 
Rare (less than 5% of patients): 
 
• Sepsis 
 
The most common serious side effects of nal-IRI +  5FU + Leucovorin   
 
• Diarrhea (occurring in 5.1% of patients) 
• Vomiting (occurring in 7.7% of patients) 
• Nausea (occurring in 3.4% of patients) 
 

ACCRU-GI-1603 
Appendix IA 
Page 10 of 17 
Phase I 
 
 
As with any medication, allergic reactions are a possibility. 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study because the 
drugs in this study can affect an unborn baby.  Women should not breastfeed a baby while on this study.  
It is important you understand that you need to use birth control while on this study.  Check with your  
 
healthcare provider about what kind of birth control methods to use and how long to use them.  Some 
methods might not be approved for use in this study.  
 
Risks of CT scans and MRIs:   This research study involves exposure to radiation from up to 6 CT scans 
per year. The CT scans that are to be performed as part of this study are considered standard of care and 
would be done regardless of your participation in this research study. This radiation may involve low risk 
of a later cancer; however, we believe that this risk is not clinically relevant. If you have any questions 
regarding the use of radiation or the risk involved, please consult the physician conducting this study.  
 
Risks of Blood draws and intravenous (IV) infusions: Drawing of blood or insertion of an intravenous 
catheter to infuse a drug may cause local pain, swelling, bruising, bleeding, or (rarely) infection at the 
place where your blood is drawn. The decision to use a catheter (a thin tube) for blood collecting is made 
by the study staff. The study staff will explain the catheter to you if its use is necessary.  
 
While you are taking part in this study, you are at risk for the above-mentioned side effects. You should 
talk to the researcher and/or your medical doctor about these side effects. There also may be other side 
effects that are not known. Side effects may range from mild to life-threatening.. Many side effects go 
away shortly after the drugs are stopped, but in some cases side effects can be serious, long lasting, or 
may never go away.  
 
For more information about risks and side effects, ask your study doctor. 
 
Electrocardiograms (ECG): This procedure requires you to lie still for a few minutes. The ECG records 
the rhythm and electrical activity of your heart. Small sticky patches called electrodes are placed on your 
arms, legs, and chest and connected by wires to an ECG recording machine to record the rhythm and 
electrical activity of your heart. The information is recorded and printed onto paper. The whole test takes 
about five minutes and is completely painless. 
 
Are there benefits to taking part in the research study? 
 
Taking part in this study may or may not make your health better.  While doctors hope the combination of 
nal-IRI + 5-FU + leucovorin + rucaparib will be more useful against cancer compared to the usual 
treatment, there is no proof of this yet.  We do know that the information from this study will help doctors 
learn more about using this drug combination as a treatment for cancer.  This information could help 
future cancer patients. 
 
What other choices do you have if you do not take part in this research study? 
 
You do not have to be in this study to receive treatment for your cancer. 
 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 

ACCRU-GI-1603 
Appendix IA 
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Phase I 
 
 
• Taking part in another study 
• Getting no treatment 
• 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, 
appetite problems and other problems caused by the cancer.  It does not treat the cancer directly, 
but instead tries to improve how you feel.  Comfort care tries to keep you as active and 
comfortable as possible.   
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
Will my medical information be kept private? 
 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given out if 
required by law.  If information from this study is published or presented at scientific meetings, your 
name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, and data 
analysis include: 
• Academic and Community Cancer Research United (ACCRU) 
• Government agencies, like the Food and Drug Administration (FDA), involved in keeping 
research safe for people 
• Institutional Review Boards 
• Clovis Oncology and their 3rd party collaborator  
• Ipsen Group 
 
A description of this clinical trial will be available on 
as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of study results.  You can search this Web site at any time. 
 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation found at 
21 CFR 50.25(c) and must be included verbatim in all informed consent documents. The text in this 
paragraph cannot be revised.] 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the 
local institution.  The regulations may or may not be included in the informed consent form depending on 
local institutional policy.] 
 
What are the costs of taking part in this research study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating 
your cancer in this study.  Some health plans will not pay these costs for people taking part in studies.  
Check with your health plan or insurance company to find out what they will pay for.  Taking part in this 
study may or may not cost your insurance company more than the cost of getting regular cancer treatment.  
 
You won’t need to pay for tests and procedures which are done just for this research study. These tests and 
procedures are: 
• Research blood tests 
• Submission of mandatory tumor tissue samples for research purposes 

ACCRU-GI-1603 
Appendix IA 
Page 12 of 17 
Phase I 
 
 
 
The study agents, rucaparib and nal-IRI, will be provided free of charge while you are taking part in this 
study.  However, if you should need to take the study agent much longer than usual, the stock of free 
study agent could run out.  If the free supply runs out, your study doctor will discuss with you how to get 
more drug from the manufacturer.  You may be asked to pay for it. 
 
The study agents, 5-FU and leucovorin, can be bought with a prescription.  You and/or your health plan 
will need to pay for all costs associated with this treatment.  You and/or your health plan will also have to pay 
for other drugs or treatment that are given to help control side effects as well as the cost of tests or exams to 
evaluate possible side effects. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at 
  You can print a 
copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send 
you a free copy. 
 
What happens if I am injured because I took part in this research study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel 
that you have been injured because of taking part in this study.  You can tell the doctor in person or call 
him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your 
health plan will be charged for this treatment.   The study will not pay for medical treatment.   
 
What are my rights if I take part in this research study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the 
study.  If you decide to take part in this study, you may leave the study at any time.   No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits.  
Leaving the study will not affect your medical care.  You can still get your medical care from our 
institution.    
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by 
signing this form.   
 
 
Who can answer questions about the research study? 

ACCRU-GI-1603 
Appendix IA 
Page 13 of 17 
Phase I 
 
 
 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact 
your study doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ 
[name of center] Institutional Review Board (a group of people who review the research to protect your 
rights) at __________________ (telephone number).  [Note to Local Investigator: Contact information 
for patient representatives or other individuals in a local institution who are not on the IRB or research 
team but take calls regarding clinical trial questions can be listed here.]    
 
Please note:  This section of the informed consent form is about additional research studies that are being 
done with people who are taking part in the main study.   
About Using Biological Samples for Research 
We would like to keep some of the blood and tissue that is left over for future research.  If you agree, this 
blood and tissue will be kept and may be used in research to learn more about cancer and other diseases.  
Please read the online booklet called "Providing Your Tissue for Research: What You Need To Know," to 
learn more about tissue research: 
  
Your blood and tissue may be helpful for research whether you do or do not have cancer.  The research 
that may be done with your blood and tissue is not designed specifically to help you.  It might help people 
who have cancer and other diseases in the future.  
Reports about research done with your blood and tissue will not be given to you or your doctor.  These 
reports will not be put in your health record.  The research will not have an effect on your care.  
Things to Think About   
The choice to let us keep the blood and tissue for future research is up to you.  No matter what you decide 
to do, it will not affect your care.  
If you decide now that your blood and tissue can be kept for research, you can change your mind at any 
time.  Just contact us and let us know that you do not want us to use your tissue.  Then any blood and 
tissue that remains will no longer be used for research.  
In the future, people who do research may need to know more about your health.  While ACCRU may 
give them reports about your health, it will not give them your name, address, phone number, or any other 
information that will let the researchers know who you are.  
Sometimes blood and tissue is used for genetic research (about diseases that are passed on in families).  
Even if your blood and tissue is used for this kind of research, the results will not be put in your health 
records.   
Your blood and tissue will be used only for research and will not be sold.  The research done with your 
blood and tissue may help to develop new products in the future.  

ACCRU-GI-1603 
Appendix IA 
Page 14 of 17 
Phase I 
 
 
Benefits  
The benefits of research using blood and tissue include learning more about what causes cancer and other 
diseases, how to prevent them, and how to treat them.  
 
Risks  
The greatest risk to you is the release of information from your health records.  We will do our best to 
make sure that your personal information will be kept private.  The chance that this information will be 
given to someone else is very small.  
 
Making Your Choice  
Please read each sentence below and think about your choice.  After reading each sentence, circle "Yes" 
or "No".  If you have any questions, please talk to your doctor or nurse, or call our research review board 
at the IRB's phone number.  
No matter what you decide to do, it will not affect your care. 
1. My blood sample(s) may be kept for use in future research to learn about, prevent, or treat cancer.  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
2. My blood sample(s) may be kept for use in future research to learn about, prevent or treat other health 
problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
3. My tissue sample(s) may be kept for use in future research to learn about, prevent, or treat cancer.  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
4. My tissue sample(s) may be kept for use in future research to learn about, prevent or treat other health 
problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
 
If you want your sample(s) destroyed at any time, write to the Secretary of the ___________________ Institutional 
Review Board ____________________________________________.   
ACCRU has the right to end storage of the sample(s) without telling you.  
 
The sample(s) will be the property of ACCRU.  Outside researchers may one day ask for a part of your sample(s) 
for studies now or future studies. 
 
How do outside researchers get the sample? 
Researchers from universities, hospitals, and other health organizations do research using blood and tissue.  They 
may call ACCRU and ask for samples for their studies.  ACCRU looks at the way that these studies will be done, 
and decides if any of the samples can be used.  ACCRU sends the samples and some information about you to the 
researcher.  ACCRU will not send your name, address, phone number, social security number, or any other 
identifying information to the researcher.  If you allow your sample(s) to be given to outside researchers, it will be 
given to them with a code number.  If researchers outside ACCRU use the sample(s) for future research, they will 

ACCRU-GI-1603 
Appendix IA 
Page 15 of 17 
Phase I 
 
 
decide if you will be contacted and, if so, they would have to contact the researchers at ACCRU.  Then ACCRU 
will contact the clinic where you registered for this study, who will contact you. 
 
 

ACCRU-GI-1603 
Appendix IA 
Page 16 of 17 
Phase I 
 
 
 
Please read the following statements and mark your choice: 
 
I permit ACCRU to give my sample(s) to outside researchers: 
 
  Yes 
 
  No  
Please initial here: 
 
 
Date: 
 
 
 
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
  
 
You may also visit the NCI Web site at 
 
 
• For NCI’s clinical trials information, go to: 
 
 
• For NCI’s general information about cancer, go to 
 
 
You will get a copy of this form.  If you want more information about this study, ask your study doctor. 
 

ACCRU-GI-1603 
Appendix IA 
Page 17 of 17 
Phase I 
 
 
Signature 
 
I have been given a copy of all __ pages of this form.  I have read it or it has been read to me.  I 
understand the information and have had my questions answered.  I agree to take part in this study. 
 
 
Printed Participant Name: __________________________________________ 
 
 
Participant Signature: ______________________________________________ 
 
 
Date: _____________________________________ 
 
 
Printed name of person obtaining informed consent:  
 
__________________________________________ 
 
 
Signature of person obtaining informed consent: 
 
___________________________________________ 
 
 
Date _____________________________________ 
 
 
 
 
 
 
 
 
 
 
This model informed consent form has been reviewed by the ACCRU and is the official consent document for this 
study.  Local IRB changes to this document are allowed.  Sections “What are the risks of the research study” or 
“What other choices do I have if I don’t take part in this research study?” should always be used in their entirety if 
possible.  Editorial changes to these sections may be made as long as they do not change information or intent.  If 
the institutional IRB insists on making deletions or more substantive modifications to these sections, they may be 
justified in writing by the investigator and approved by the IRB.  Under these circumstances, the revised language 
and justification must be forwarded to the Academic and Community Cancer Research United (ACCRU) 
Operations Office for approval before a patient may be registered to this study. 
 
Consent forms will have to be modified for each institution as it relates to where information may be obtained on 
the conduct of the study or research subject.  This information should be specific for each institution. 
 

ACCRU-GI-1603 
Appendix IB 
 
Phase Ib 
 
 
ACCRU Informed Consent Template for Cancer Treatment 
Trials 
(English Language) 
 
*NOTES FOR LOCAL INVESTIGATORS: [NOTE: Retain this section and asterisk item below for 
ACCRU model consents] 
• The goal of the informed consent process is to provide people with sufficient information for 
making informed choices.   The informed consent form provides a summary of the clinical study 
and the individual's rights as a research participant.  It serves as a starting point for the necessary 
exchange of information between the investigator and potential research participant.   
• A blank line, __________, indicates that the local investigator should provide the appropriate 
information before the document is reviewed with the prospective research participant.  
• Suggestion for Local Investigators:  The NCI web site has information explaining clinical trials.  
The web page is entitled: "Taking Part in Cancer Treatment Research Studies."  A free PDF may 
be downloaded from the NCI web site:  
 
• Optional feature for Local Investigators: Reference and attach drug sheets, pharmaceutical 
information for the public, or other material on risks.  Check with your local IRB regarding review 
of additional materials. 
 
*These notes for {authors and} investigators are instructional and should not be included in the informed 
consent form given to the prospective research participant.  
 

ACCRU-GI-1603 
Appendix IB 
Page 1 of 17 
Phase Ib 
 
ACCRU-GI-1603, Phase I/Ib Study of Irinotecan Liposome (nal-
IRI), Fluorouracil and Rucaparib in the Treatment of Select 
Gastrointestinal Metastatic Malignancies Followed by a Phase Ib of 
First and Second Line Treatment of both Unselected and Selected 
Patients with Metastatic Adenocarcinoma of the Pancreas then 
Followed by a Phase II Study of First Line Treatment of Selected 
Patients with Metastatic Adenocarcinoma of the Pancreas with 
Genomic Markers (Signature) of Homologous Recombination 
Deficiency (HRD) 
 
This is an important form.  Please read it carefully.  It tells you what you need to know about 
this research study.  If you agree to take part in this study, you need to sign this form.  Your 
signature means that you have been told about the study and what the risks are.  Your 
signature on this form also means that you want to take part in this study. 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.   Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
 
You are being asked to take part in this research study because you have cancer of the pancreas 
or gastroesophageal cancer that has spread to other parts of your body (metastasized), and you 
have not received more than two other types of treatment before taking part in this study. 
 
Why is this research study being done? 
 
This study is being done in three parts:  Phase I, Phase 1b and Phase II. You are being asked to 
take part in the Phase Ib portion of the study. The purpose of this Phase Ib research study is to 
learn more about the safety and side effects of the combination of nal-IRI +  rucaparib +  5-FU in 
patients who have pancreatic cancer  that has spread to other parts of the body (metastasized) , 
and who have received no more than one treatment before taking part in this study. 
 
How many people will take part in the research study? 
 
About 40 people will take part in this Phase Ib study: 28 patients with cancer of the pancreas 
with either unknown mutation (a change in the usual DNA sequence of a gene that prevents the 
gene from working normally) status or non-HRD and 12 patients with cancer of the pancreas 
with known HR deficiency.   
 
What will happen if I take part in this research study? 

ACCRU-GI-1603 
Appendix IB 
Page 2 of 17 
Phase Ib 
 
 
Before you begin the study …  
 
Within 1 to 3 weeks before study registration – You will need to have the following exams, 
tests or procedures to find out if you can be in the study.  These exams, tests or procedures are 
part of regular cancer care and may be done even if you do not join the study.  If you have had 
some of them recently, they may not need to be repeated.  This will be up to your study doctor. 
 
• Medical history and physical exam; your doctor will also ask how well you perform 
activities in your daily life. 
• A check to see if any of the side effects that may be caused by the study drugs are 
already present. 
• Routine blood tests – equal to about the amount in 2 tablespoons will be taken from a 
vein in your arm. 
• Research blood tests – when you have the routine blood test done, we will also take 
between 2 teaspoons and 4 tablespoons of additional blood for research and banking for 
future research.  Giving this extra blood is required if you participate in this study. 
• CT scan or MRI to measure your tumor  
• Electrocardiogram (ECG) to look at your heart and heart valves to see how well they 
are working. 
• A pregnancy test done by taking a blood sample from a vein in your arm within 21 
days of being registered on the study, and again within 7 days of being registered – if 
you are a woman of childbearing potential. The pregnancy test results must be 
negative in order for you to continue on the study. 
• Collection of a tumor sample from your previous surgery or biopsy for research 
purposes; no additional tumor tissue will be taken from you during this study.  
• This sample will be used to look for genes in your tumor that will predict the 
effectiveness of the study drugs in future patients with pancreatic or gastroesophageal 
cancer treated with the combination of nal-IRI +  rucaparib + 5-FU.  
 
During the study …  
 
If the exams, tests and procedures show that you can be in the study, and you choose to 
take part, then you will need the following tests and procedures.  They are part of regular 
cancer care.  
 
• Medical history and physical exam; your doctor will also ask how well you perform 
activities in your daily life and review your Patient Medication Diary. 
• A check to see if any of the side effects that may be caused by the study drugs are 
already present. 
• Routine blood tests – equal to about the amount in 2 tablespoons will be taken from a 
vein in your arm. 
• CT scan or MRI to measure your tumor  

ACCRU-GI-1603 
Appendix IB 
Page 3 of 17 
Phase Ib 
 
• A pregnancy test done by taking a blood sample from a vein in your arm every 28 days 
before each treatment (if you are a woman of childbearing potential). The pregnancy 
test results must be negative in order for you to continue on the study. 
 
You will need the following tests and procedures that are part of regular cancer care.   They 
are being done more often because you are in this study.   
 
• A pregnancy test done by taking a blood sample from a vein in your arm every 28 days 
before each treatment (if you are a woman of childbearing potential). The pregnancy 
test results must be negative in order for you to continue on the study. 
 
You will need these tests and procedures that are either being tested in this study or being 
done to see how the study is affecting your body. 
 
• Research blood tests – when you have the routine blood test done, we will also take 
between 2 teaspoons and 4 tablespoons of additional blood for research and banking for 
future research.  Giving this extra blood is required if you participate in this study. 
 
This research will explore possible genetic or inherited reasons for how patients respond to 
medications. Your blood and tissue samples contain genes, which are made up of DNA and 
proteins that serve as the "instruction book" for the cells that make up our bodies. Your samples 
will help us study how genes interact with other factors to influence the development and 
treatment of diseases. Because the genetic tests in this study are not used for regular medical 
care, you will not be told the results of the test(s), and the test results will not be put in your 
medical record. 
 
There is more information about these research tests at the end of this form. 
 
Once it is determined that you are eligible for the study and agree to take part, you will 
begin treatment. Treatment takes place over three 28-day periods; each 28-day period is called 
a cycle.  
 
Treatment during each cycle includes the following: 
 
On days 1 and 15 of every 28-day cycle, about 30-60 minutes before receiving the study 
drugs noted below, you will be given medications (dexamethasone (or similar) and 
ondansetron (or similar)) through a needle placed in your arm (also referred to as an IV 
(intravenous)) to make side effects less serious and less uncomfortable. These medications 
are sometimes known as pretreatment medications. 
 
On days 1 and 15, after receiving the pretreatment medications, you will receive nal-IRI 
+ 5-FU. These drugs will be given to you through the IV.   
 
In addition to the IV study drugs, you will also take the study drug, rucaparib, in pill form, 
by mouth, two times every day beginning on day 4 of the first week and continue through 
day 13. You will not take this drug on days 14-17. On day 18 you will start taking rucaparib 

ACCRU-GI-1603 
Appendix IB 
Page 4 of 17 
Phase Ib 
 
again, and continue taking through 27, then stop taking this drug again on day 28 (see study 
calendar below).   
 
If you have side effects that get too bad at any time during these cycles, the doses listed above 
will be decreased until the side effects get better. Treatment may discontinue completely if side 
effects are too bad or your cancer gets worse. 
 
Medication Diary 
 
You will be asked to keep a daily record (Patient Medication Diary) of when you take the study 
medication, rucaparib, and every day write down the day and time you take the medication. If 
you notice any side effects, you can include this information in the Comments section of the 
diary. 
Study Calendar 
 
You will receive nal-IRI + 5-FU + rucaparib in this study every one to two weeks over a 28-day 
period. This 28-day period of time is called a cycle.  The cycle will be repeated 3 times.  The chart 
below shows what will happen to you during each Cycle, as explained previously.  The left-hand 
column shows the day in the cycle and the right-hand column tells you what to do on that day. 
  
Day  
 
What you do 
Up to 21 days 
before starting 
treatment 
• Medical history and physical exam; your doctor will also ask how well you 
perform activities in your daily life. 
• A check to see if any of the side effects that may be caused by the study 
drugs are already present. 
• Routine blood tests  
• CT scan or MRI  
• Electrocardiogram (ECG)  
• Mandatory submission of a tumor sample from your previous surgery or 
biopsy  
Up to 7 days 
before starting 
treatment 
• Pregnancy test (only if you are a woman of childbearing potential) 
• Mandatory research blood tests 
Day 1 of each 
cycle 
• Prior to dosing - Pregnancy test (only if you are a woman of childbearing 
potential) 
• Medical history and physical exam; your doctor will also ask how well you 
perform activities in your daily life. 
• A check to see if you are having any side effects from study drugs. 
• Review Patient Medication Diary 
• Routine blood tests  
• ECG 
• Receive pretreatment medications through an IV.  
• Receive nal-IRI, 5-FU through an IV.   
Days  4-13 
• Take rucaparib, in pill form, by mouth, two times every day beginning on 
day 4 of the first week and continue through day 10. 

ACCRU-GI-1603 
Appendix IB 
Page 5 of 17 
Phase Ib 
 
Days 14-17  
• Stop taking rucaparib. 
 

ACCRU-GI-1603 
Appendix IB 
Page 6 of 17 
Phase Ib 
 
Study Calendar – Continued 
 
Day 
 
 
What you do 
Day 15 
• Medical history and physical exam; your doctor will also ask how well you 
perform activities in your daily life. 
• A check to see if you are having any side effects from study drugs. 
• Routine blood tests  
• Receive pretreatment medications through an IV.  
• Receive nal-IRI, 5-FU through an IV.   
Days 18-27  
• Take rucaparib, in pill form, by mouth, two times every day beginning on 
day 15 and continue through day 21. 
Day 28 
• Stop taking rucaparib. 
• On one of these days (Day 22 – 28) before every odd-numbered cycle 
(before cycle 3, cycle 5, etc.), do the following: 
 CT scan or MRI to measure your tumor  
 Routine blood tests 
Cycle 2 
• Repeat Days 1-28 as above 
Cycle 3 
• Repeat Days 1-28 as above 
End of 
Treatment (after 
you complete the 
full treatment, or 
if your disease 
progresses or 
you stop the 
treatment for any 
reason) 
• Medical history and physical exam; your doctor will also ask how well you 
perform activities in your daily life. 
• A check to see if you are having any side effects from study drugs. 
• Review Patient Medication Diary 
• Routine blood tests 
• Mandatory research blood tests 
• CT scan or MRI 
 
When you are finished taking the study drugs… 
 
Within about 30 days after your last treatment, the following tests and procedures will be done:  
 
• Medical history and physical exam; your doctor will also ask how well you perform 
activities in your daily life and review your Patient Medication Diary. 
• A check to see if you are having any side effects from study drugs. 
• Routine blood tests – equal to about the amount in 2 tablespoons will be taken from a 
vein in your arm. 
• Research blood tests – when you have the routine blood test done, we will also take 
between 2 teaspoons and 4 tablespoons of additional blood for research and banking for 
future research.   
 
 

ACCRU-GI-1603 
Appendix IB 
Page 7 of 17 
Phase Ib 
 
How long will you be in the research study? 
 
You will continue to receive the combination of nal-IRI + 5-FU and rucaparib for about 3 
months, or until your disease gets worse, or you have side effects that you are unable to tolerate.   
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
 
After you are finished taking the study drugs, the study doctor will ask you to visit the office for 
follow-up exams for about 3 years. 
 
Can I stop being in the research study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
nal-IRI, 5-FUand rucaparib can be evaluated by your doctor.  Another reason to tell your doctor 
that you are thinking about stopping is to discuss what follow-up care and testing could be most 
helpful for you. 
 
What side effects or risks can I expect from being in the research study? 
 
If you have not previously received standard treatments for your cancer and decide to take part in 
this research study, you are declining standard treatment and the potential benefits of these 
standard treatments. 
 
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  
Side effects may be mild or very serious.  Your health care team may give you medicines to help 
lessen side effects.  Many side effects go away soon after you stop taking the combination of nal-
IRI + 5-FU + rucaparib.  In some cases, side effects can be serious, long lasting, or may never go 
away. There also is a risk of death.   
 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study.   
Oral rucaparib is an experimental drug that may have side effects that cannot be predicted at this 
time.    
Rare or unknown side effects could possibly occur, including life-threatening reactions.   
Common Side Effects 
The following is a list of the most commonly reported side effects reported by patients who have 
received rucaparib, whether taking rucaparib alone or at the same time they were receiving 
chemotherapy: 

ACCRU-GI-1603 
Appendix IB 
Page 8 of 17 
Phase Ib 
 
• Low blood counts (especially of the white blood cells, but sometimes of red blood cells 
and platelets).  Sometimes fever occurs with the low blood counts   
o A low white blood cell count puts you at higher risk for infection.  If you have a 
temperature higher than 100.4°F (38.0°C) at any time during the study, you must 
tell the study doctor immediately.   
o A low red blood cell count may make you feel tired or dizzy.  If you feel dizzy 
while taking rucaparib, you should avoid potentially hazardous tasks such as 
driving or operating machinery. 
o A low platelet count affects the ability of your blood to clot and could lead to 
bleeding events 
• Stomach-related effects such as nausea, vomiting, diarrhea, loss of appetite, heartburn, 
and constipation 
• Feeling tired (Fatigue) 
• Headache 
• Abdominal pain 
• Elevated liver enzymes 
• Dizziness 
• Bad taste in mouth (or altered sense of taste) 
• Increased sensitivity to sunlight- please use appropriate sun protection  
• Increased serum creatinine 
• Increase in cholesterol 
• Rash  
• Pruritis (itchy skin) 
• Dyspnea (difficult or labored breathing) 
• Due to the risk of permanent damage or death to a developing embryo/fetus, both women 
of childbearing potential and men and their opposite sex partners of reproductive 
potential should use contraception during dosing and for 6 months after completing 
treatment with rucaparib. 
 
Less Common Side Effects (>1% - <5% of patients)  
 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been reported in a 
very small number of patients treated with rucaparib. MDS is a pre-cancerous condition where 
the bone marrow is not as good at producing blood cells (red and/or white blood cells and/or 
platelets) as it was before. People with MDS need transfusions (red blood cells and/or platelets) 
and/or other treatments. In some cases, MDS will progress to AML, which is a cancer of the 
bone marrow where more abnormal and immature white blood cells (also called blasts) are made 
than normal white blood cells. People with AML need treatment with chemotherapy and/or a 
transplant. Patients may develop AML without first being diagnosed with MDS. MDS/AML can 
be fatal and led to death in 2 patients on rucaparib (0.5%). 
 
Events of MDS and AML have also been reported with PARP inhibitors similar to rucaparib. At 
this time it is not known whether PARP inhibitors cause MDS or AML or if these developed as a 
result of previous chemotherapy these patients received. Your Study Doctor will closely monitor 
your blood cell levels during treatment. If he/she has any concerns about your blood counts you 

ACCRU-GI-1603 
Appendix IB 
Page 9 of 17 
Phase Ib 
 
may be asked to have a biopsy of your bone marrow. 
 
If you develop low blood counts, or if you have any other significant side effects, you may need 
to stop taking rucaparib until you recover from these side effects.  The study doctor may also 
decide to lower your dose of rucaparib if you experience certain side effects.  
Pneumonitis (inflammation of the lung tissue) has been designated by Clovis as an adverse event 
of special interest. Pneumonitis has been reported with PARP inhibitor treatment, including in 
clinical studies evaluating rucaparib. To date, pneumonitis cases were reported in approximately 
0.6% patients. In clinical studies evaluating rucaparib as monotherapy, cases of pneumonitis 
were reported in approximately 0.1% patients. Currently, however, there is a lack of 
understanding of a mechanistic link between pneumonitis and PARP inhibitor treatment. Cases 
of pneumonitis lack a consistent clinical pattern, and are often confounded with risk factors, such 
as cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, and/or 
previous chemotherapy and radiotherapy. 
 
Allergic Reactions 
As with any drug, it is possible that you could have allergic reactions to rucaparib, such as 
itching, skin rash, facial swelling, and/or a severe or sudden drop in blood pressure.  A sudden 
drop in blood pressure could lead to shock with loss of consciousness and/or possible seizures, 
including the possibility of death.  If you have any of the above symptoms, seek medical 
attention right away. 
 
Risks and side effects related to nal-IRI + 5-FU include those which are: 
 
Likely  (more than 10%) 
 
In a clinical trial evaluating the effectiveness of nal-IRI in the treatment of metastatic pancreatic 
cancer, 117 patients received nal-IRI in combination with 5-FU . In this group of patients, the 
most common side effects that happened in at least 12 of the 117 patients (more than 10% of 
those patients) included the following: 
 
• Diarrhea 
• Vomiting 
• Nausea 
• Decreased appetite 
• Fatigue (tiredness) 
• Anemia (decreased red blood cells or hemoglobin, which may cause tiredness and lack 
of energy) 
• Fever 
• Neutropenia (decrease in a type of white blood cells called neutrophils, may increase the 
risks of infections) 
• Abdominal pain 

ACCRU-GI-1603 
Appendix IB 
Page 10 of 17 
Phase Ib 
 
• Constipation 
• Asthenia (lack of energy) 
• Weight loss 
• Leukopenia (decrease in white blood cells) 
• Hair loss (alopecia) 
• Stomatitis (inflammation of the lining of the mouth) 
• Back pain 
• Dizziness 
• Hypokalemia (decrease in blood potassium levels) 
• Peripheral edema (collection of fluid in the tissues of the body) 
• Mucosal inflammation (lining of mouth, esophagus, stomach and intestines) 
• Thrombocytopenia (a decrease in platelets (particles that help the blood to clot, may 
cause bruising or bleeding) 
 
Less Likely (more than 5% of those patients) 
 
The less commonly seen side effects that occurred in at least 6 of the 117 patients (more than 5% 
of those patients) were: 
 
• Upper abdominal pain 
• Dehydration 
• Hypomagnesemia (decrease in blood magnesium levels) 
• Hypoalbuminemia (decrease in a type of blood protein called albumin) 
 
Rare (less than 5% of those patients): 
 
• Sepsis 
 
The most common serious side effects of nal-IRI +  5FU    
 
• Diarrhea (occurring in 5.1% of patients) 
• Vomiting (occurring in 7.7% of patients) 
• Nausea (occurring in 3.4% of patients) 
 
As with any medication, allergic reactions are a possibility. 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important you understand that you need to use birth control while on 
this study.  Check with your health care provider about what kind of birth control methods to use 
and how long to use them.  Some methods might not be approved for use in this study.  
 
Risks of CT scans and MRIs:  CT scans or MRIs may be done to check your tumor. When 
these are done you will be exposed to low doses of radiation. These doses of radiation that you 
will receive have a low risk of harmful effects. These types of scans are also commonly used to 

ACCRU-GI-1603 
Appendix IB 
Page 11 of 17 
Phase Ib 
 
monitor cancer. 
 
Risks of Blood draws and intravenous (IV) infusions: Drawing of blood or insertion of an 
intravenous catheter to infuse a drug may cause local pain, swelling, bruising, bleeding, or 
(rarely) infection at the place where your blood is drawn. The decision to use a catheter (a thin 
tube) for blood collecting is made by the study staff. The study staff will explain the catheter to 
you if its use is necessary.  
 
While you are taking part in this study, you are at risk for the above-mentioned side effects. You 
should talk to the researcher and/or your medical doctor about these side effects. There also may 
be other side effects that are not known. Side effects may range from mild to life-threatening..  
 
Many side effects go away shortly after the drugs are stopped, but in some cases side effects can 
be serious, long lasting, or may never go away.  
 
For more information about risks and side effects, ask your study doctor. 
 
Electrocardiograms (ECG): This procedure requires you to lie still for a few minutes. The 
ECG records the rhythm and electrical activity of your heart. Small sticky patches called 
electrodes are placed on your arms, legs, and chest and connected by wires to an ECG recording 
machine to record the rhythm and electrical activity of your heart. The information is recorded 
and printed onto paper. The whole test takes about five minutes and is completely painless. 
 
Are there benefits to taking part in the research study? 
 
Taking part in this study may or may not make your health better.  While doctors hope the 
combination of nal-IRI + 5-FU + rucaparib will be more useful against cancer compared to the 
usual treatment, there is no proof of this yet.  We do know that the information from this study 
will help doctors learn more about using this drug combination as a treatment for cancer.  This 
information could help future cancer patients. 
 
What other choices do you have if you do not take part in this research study? 
 
You do not have to be in this study to receive treatment for your cancer. 
 
Your other choices may include: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting no treatment 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.   
 
Talk to your doctor about your choices before you decide if you will take part in this study. 

ACCRU-GI-1603 
Appendix IB 
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Phase Ib 
 
 
Will my medical information be kept private? 
 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 
• Academic and Community Cancer Research United (ACCRU) 
• Government agencies, like the Food and Drug Administration (FDA), involved in 
keeping research safe for people 
• Institutional Review Boards 
• Clovis Oncology and their 3rd party collaborator 
• Ipsen Group 
 
A description of this clinical trial will be available on 
as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of study results.  You can search this Web site at any time. 
 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation 
found at 21 CFR 50.25(c) and must be included verbatim in all informed consent documents. The 
text in this paragraph cannot be revised.] 
 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
What are the costs of taking part in this research study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
You won’t need to pay for tests and procedures which are done just for this research study. These 
tests and procedures are: 
• Research blood tests 
• Submission of mandatory tumor tissue samples for research purposes 
 
The study agents, rucaparib and nal-IRI, will be provided free of charge while you are taking part 
in this study.  However, if you should need to take the study agent much longer than usual, the 

ACCRU-GI-1603 
Appendix IB 
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Phase Ib 
 
stock of free study agent could run out.  If the free supply runs out, your study doctor will 
discuss with you how to get more drug from the manufacturer.  You may be asked to pay for it. 
 
The study agent 5-FU can be bought with a prescription.  You and/or your health plan will need 
to pay for all costs associated with this treatment.  You and/or your health plan will also have to pay 
for other drugs or treatment that are given to help control side effects as well as the cost of tests or exams 
to evaluate possible side effects. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at 
    You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
What happens if I am injured because I took part in this research study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.   
 
What are my rights if I take part in this research study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer questions about the research study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 

ACCRU-GI-1603 
Appendix IB 
Page 14 of 17 
Phase Ib 
 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number).  
[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.]    
Please note:  This section of the informed consent form is about additional research studies that 
are being done with people who are taking part in the main study.   
 
About Using Biological Samples for Research 
We would like to keep some of the blood and tissue that is left over for future research.  If you 
agree, this blood and tissue will be kept and may be used in research to learn more about cancer 
and other diseases.  Please read the online booklet called "Providing Your Tissue for Research: 
What You Need To Know," to learn more about tissue research: 
  
Your blood and tissue may be helpful for research whether you do or do not have cancer.  The 
research that may be done with your blood and tissue is not designed specifically to help you.  It 
might help people who have cancer and other diseases in the future.  
Reports about research done with your blood and tissue will not be given to you or your doctor.  
These reports will not be put in your health record.  The research will not have an effect on your 
care.  
Things to Think About   
The choice to let us keep the blood and tissue for future research is up to you.  No matter what 
you decide to do, it will not affect your care.  
If you decide now that your blood and tissue can be kept for research, you can change your mind 
at any time.  Just contact us and let us know that you do not want us to use your blood and tissue.  
Then any blood and tissue that remains will no longer be used for research.  
In the future, people who do research may need to know more about your health.  While ACCRU  
may give them reports about your health, it will not give them your name, address, phone 
number, or any other information that will let the researchers know who you are.  
Sometimes blood and tissue is used for genetic research (about diseases that are passed on in 
families).  Even if your blood and tissue is used for this kind of research, the results will not be 
put in your health records.   
Your blood and tissue will be used only for research and will not be sold.  The research done 
with your blood and tissue may help to develop new products in the future.  

ACCRU-GI-1603 
Appendix IB 
Page 15 of 17 
Phase Ib 
 
Benefits  
The benefits of research using blood and tissue include learning more about what causes cancer 
and other diseases, how to prevent them, and how to treat them.  
 
Risks  
The greatest risk to you is the release of information from your health records.  We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
Making Your Choice  
Please read each sentence below and think about your choice.  After reading each sentence, 
circle "Yes" or "No".  If you have any questions, please talk to your doctor or nurse, or call our 
research review board at the IRB's phone number.  
No matter what you decide to do, it will not affect your care. 
1. My blood sample(s) may be kept for use in future research to learn about, prevent, or treat 
cancer.  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
2. My blood sample(s) may be kept for use in future research to learn about, prevent or treat 
other health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
3. My tissue sample(s) may be kept for use in future research to learn about, prevent, or treat 
cancer.  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
4. My tissue sample(s) may be kept for use in future research to learn about, prevent or treat 
other health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
 
  Yes 
  No  
Please initial here: ________  
Date: ________ 
 
If you want your sample(s) destroyed at any time, write to the Secretary of the 
___________________ Institutional Review Board 
____________________________________________.   
ACCRU has the right to end storage of the sample(s) without telling you.  
 
The sample(s) will be the property of ACCRU.  Outside researchers may one day ask for a part 
of your sample(s) for studies now or future studies. 
 
How do outside researchers get the sample? 
Researchers from universities, hospitals, and other health organizations do research using blood 
and tissue.  They may call ACCRU and ask for samples for their studies.  ACCRU looks at the 

ACCRU-GI-1603 
Appendix IB 
Page 16 of 17 
Phase Ib 
 
way that these studies will be done, and decides if any of the samples can be used.  ACCRU 
sends the samples and some information about you to the researcher.  ACCRU will not send your 
name, address, phone number, social security number, or any other identifying information to the 
researcher.  If you allow your sample(s) to be given to outside researchers, it will be given to 
them with a code number.  If researchers outside ACCRU use the sample(s) for future research, 
they will decide if you will be contacted and, if so, they would have to contact the researchers at 
ACCRU.  Then ACCRU will contact the clinic where you registered for this study, who will 
contact you. 
 
Please read the following statements and mark your choice: 
 
I permit ACCRU to give my sample(s) to outside researchers: 
 
  Yes 
 
  No  
Please initial here: 
 
 
Date: 
 
 
 
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237)  
 
You may also visit the NCI Web site at 
 
 
• For NCI’s clinical trials information, go to: 
 
 
• For NCI’s general information about cancer, go to 
 
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor. 
 

ACCRU-GI-1603 
Appendix IB 
Page 17 of 17 
Phase Ib 
 
Signature 
 
I have been given a copy of all  
 pages of this form.  I have read it or it has been read to me.  
I understand the information and have had my questions answered.  I agree to take part in this 
study. 
 
 
Printed Participant Name: __________________________________________ 
 
 
Participant Signature: ______________________________________________ 
 
 
Date: _____________________________________ 
 
 
Printed name of person obtaining informed consent:  
 
__________________________________________ 
 
 
Signature of person obtaining informed consent: 
 
___________________________________________ 
 
 
Date _____________________________________ 
 
 
 
 
 
 
 
This model informed consent form has been reviewed by the ACCRU and is the official consent 
document for this study.  Local IRB changes to this document are allowed.  Sections “What are the risks 
of the research study” or “What other choices do I have if I don’t take part in this research study?” should 
always be used in their entirety if possible.  Editorial changes to these sections may be made as long as 
they do not change information or intent.  If the institutional IRB insists on making deletions or more 
substantive modifications to these sections, they may be justified in writing by the investigator and 
approved by the IRB.  Under these circumstances, the revised language and justification must be 
forwarded to the Academic and Community Cancer Research United (ACCRU) Operations Office for 
approval before a patient may be registered to this study. 
 
Consent forms will have to be modified for each institution as it relates to where information may be 
obtained on the conduct of the study or research subject.  This information should be specific for each 
institution. 

ACCRU-GI-1603 
Appendix II 
 
Page 1 of 2 
 
Patient Medication Diary - Rucaparib 
 
 
Patient Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Number: ACCRU-GI-1603 
 
Instructions 
 
1. Please bring your Medication Diary and any empty or unused medication container(s) with you to every appointment.   
2.  Use an ink pen when completing the Medication Diary as these will be retained in our research record. 
3. Contact your physician and study coordinator any time you go into the hospital.  Your physician can advise if you should stop taking your medication or 
continue it. 
4. Every day, in the table below, record each dose as soon as you take it. Write the date and time you took the Rucaparib, and the amount (e.g., 200 mg).  
5. Indicate on the calendar below every day that you take your study medication by placing the time dose was taken on the line under the date.  
6. If you miss a dose, place a “0” under the date (morning and/or evening), but, remember to take your prescribed dose at the next regularly scheduled time. 
NOTE: If you vomit after taking the daily dose of Rucaparib, DO NOT repeat dosing. Resume taking rucaparib at the next scheduled time. Remember to 
write a comment on your diary if this happens. 
7. To correct an error or mistake, please make a single line through that entry and write your initials and date next to the error or mistake.  
8. If you have any comments or notice any side effects, please record them in the Comments section (attach an additional page of comments, if needed). 
9. Store your study drug at normal room temperature and keep out of the reach of children and pets. 
 
 
Study Medications  
MG 
Rucaparib 
MG 
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date: 
 
 
 
 
 
 
 
Dose: 
 
 
 
 
 
 
 
Time of Morning Dose 
 
AM 
AM 
AM 
AM 
AM 
AM 
AM 
Time of Evening Dose 
PM 
PM 
PM 
PM 
PM 
PM 
PM 
Comments 
 
 
 
 
 
 
 
 

ACCRU-GI-1603 
Appendix II 
 
Page 2 of 2 
 
 
 
 
 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date: 
 
 
 
 
 
 
 
Dose: 
 
 
 
 
 
 
 
Time of Morning Dose 
 
AM 
AM 
AM 
AM 
AM 
AM 
AM 
Time of Evening Dose 
PM 
PM 
PM 
PM 
PM 
PM 
PM 
Comments 
 
 
 
 
 
 
 
 
 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Date: 
 
 
 
 
 
 
 
Dose: 
 
 
 
 
 
 
 
Time of Morning Dose 
 
AM 
AM 
AM 
AM 
AM 
AM 
AM 
Time of Evening Dose 
PM 
PM 
PM 
PM 
PM 
PM 
PM 
Comments 
 
 
 
 
 
 
 
 
 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Date: 
 
 
 
 
 
 
 
Dose: 
 
 
 
 
 
 
 
Time of Morning Dose 
 
AM 
AM 
AM 
AM 
AM 
AM 
AM 
Time of Evening Dose 
PM 
PM 
PM 
PM 
PM 
PM 
PM 
Comments 
 
 
 
 
 
 
 
 
Participant Signature________________________________  
 
 
 
 
Date: ________________ 
Area Below To Be Completed By Study Staff Only 
 
Number of Pills returned: ____________ 
 
 
 
 
Study Coordinator Initials: _________________ 

ACCRU-GI-1603 
Appendix III 
 
Page 1 of 1