Phase II, Randomized, Placebo-Controlled Study of Minocycline for Reducing Symptom Burden in Patients With Colorectal Cancer
Phase: PHASE2
Conditions: Colorectal Cancer
Sponsor: M.D. Anderson Cancer Center

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Protocol Page
Phase II, randomized, placebo-controlled study of minocycline for reducing symptom 
burden in patients with colorectal cancer
2013-0323
Core Protocol Information
Short Title 
Phase II study of Minocycline for reducing symptom burden in colorectal patients
Study Chair: 
Cathy Eng
Additional Contact:
Angele K. Saleeba
Araceli G. Garcia-Gonzalez
Xin Shelley Wang
Department:
Symptom Research
Phone:
713-792-2828
Unit:
1450
Full Title: 
Phase II, randomized, placebo-controlled study of minocycline for reducing symptom burden in 
patients with colorectal cancer
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 02/15/2019
Version:
16
Submitted by:
Angele K. Saleeba--3/16/2017 11:36:38 AM
OPR Action:
Accepted by:  Yolanda Shorte -- 3/23/2017 3:16:38 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)

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Protocol Body
1.0 Objectives
1.1  
Primary Outcome
The primary objective of this protocol is to examine the clinical efficacy of minocycline in 
reducing acute peripheral neuropathy during oxaliplatin-based chemotherapy in patients with 
colorectal cancer (CRC). 
1.2  
Secondary Outcomes
1.21  To examine the clinical efficacy of minocycline in reducing fatigue during 
oxaliplatin-based chemotherapy in patients with CRC. 
1.22  To examine the impact of socioeconomic status (SES) on the clinical efficacy of 
minocycline in reducing acute peripheral neuropathy during oxaliplatin-based chemotherapy in 
patients with CRC, and to determine if the level of neuropathy is the same after patients are 
taken off study medications.  
1.23  To examine the interaction between SES and inflammation (circulating cytokines 
and activation of immune cells) and the effect of these variables on symptom severity in CRC 
patients.
1.24  To explore the relationship between objective measures of neuropathy and  
patient-reported symptom outcome measures and health status. 
2.0 Background
Despite increased public awareness and use of proven screening methods, colorectal cancer 
(CRC) is the third-most-common cancer and the second-leading cause of cancer death for men 
and women combined in the United States (Siegel et al., 2012). Oxaliplatin, a standard 
chemotherapy agent for CRC, not only confers significant clinical benefit, but also causes acute 
and chronic neurotoxicity (Grothey, 2010). As a dose-limiting toxic effect, oxaliplatin 
chemotherapy-induced peripheral neuropathy (CIPN) interferes with functional ability, causes 
distress, and persists into survivorship for thousands of patients; it also can compromise 
adherence to therapy. Nearly 40% of patients with CRC receiving oxaliplatin-based 
chemotherapy experience neuropathy that is significant enough to cause dose reduction or 
withdrawal. Although neuropathy might be seen as a small negative consequence of treatment 
compared with the prolongation of overall survival conferred by such treatment, a well-founded 
mechanistic strategy could effectively and actively manage CIPN. 
Effective management of CIPN is lacking; it is often addressed with “treatment holidays” or 
dose reductions. A paucity of research on biological attributes is a key hindrance to providing 
mechanism-driven care for treatment-related toxicity and high symptom burden. However, 
preclinical animal modeling has provided strong evidence that the common antibiotic 
minocycline has a neuroprotective effect on oxaliplatin-induced (Boyette-Davis & Dougherty, 
2011) and taxane-induced (Cata et al., 2008) hyperalgesia. Minocycline has long-lasting effects 
in preventing neuropathic pain (Padi & Kulkarni, 2008; Raghavendra et al., 2003) and 
neurodegenerative disorders (Noble et al., 2009); it was safe and effective for patients with 

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rheumatoid arthritis in a 48-week double-blind placebo-controlled trial (Tilley et al., 1995).
Others have reported that minocycline has a wide range of anti-inflammatory activity in the brain 
and peripheral nervous system, which it accomplishes by inhibiting microglial activation and 
proliferation through inhibition of the inflammation pathway (Henry et al., 2008). An increase in 
inflammation is a prime candidate for the mechanism behind increases in treatment-related 
symptoms, including CIPN. We have reviewed the evidence of the impact of inflammation on 
several cancer-related symptoms (Lee et al., 2004). The insult of cancer treatment, including 
chemotherapy, increases production of inflammatory cytokines, especially interleukin (IL)-6 and 
tumor necrosis factor (TNF) variants (Linard et al., 2004; Linard et al., 2005). Both paclitaxel 
and cisplatin are known to cause a rise in the levels of cytokines, especially IL-6, in cancer 
patients (Endo et al., 2004). High levels of IL-6 have been found in patients with inoperable lung 
cancer receiving cisplatin along with combination treatment (Mantovani et al., 2000). Cytokines 
have been suggested to have a role in the increase of IL-6 in response to paclitaxel chemotherapy 
in breast cancer (Pusztai et al., 2004), and IL-6 has been associated with reported symptoms in 
allogeneic hematopoietic stem cell transplantation and chemoradiation therapies (Wang et al., 
2008; Wang et al., 2012). Although the specific causes of CIPN remain to be fully elucidated, its 
severity may be reduced by inhibition of proinflammatory cytokines.
This project is a Phase II, two-arm, randomized, placebo-controlled study of patients with CRC 
receiving oxaliplatin-based chemotherapy. As a primary objective, we will pursue prevention 
and reduction of CIPN via broad pro-inflammatory cytokine blockade by minocycline. As 
secondary objectives, we will examine minocycline’s efficacy in reducing the severity of fatigue 
and also compare its efficacy in patients seen at a private/academic cancer center (The 
University of Texas MD Anderson Cancer Center) versus a public hospital ( Lyndon B. Johnson 
General Hospital [LBJ]) where patients are highly likely to have low socioeconomic status 
(SES). Patients of low SES, often referred to as the medically underserved, are at greater risk for 
severe symptoms (Cleeland et al., 2011). Specifically, we have found that CIPN is 
disproportionally more severe in the medically underserved, and the control of CIPN should 
therefore be even more important for this group of patients. In several ongoing Phase II, 
randomized studies of minocycline in patients with pancreatic cancer, non-small cell lung cancer 
(NSCLC), or head and neck cancer at MD Anderson, we have found no increased toxicity for 
patients.
Our proposed study is innovative because (1) little literature is focused on the biobehavioral 
mechanisms underlying disease-related symptoms and the toxic effects of treatment in medically 
underserved cancer patients, and (2) this study provides a direct test of the effects of modulating 
inflammation as a potential treatment for CIPN in CRC, with potentially greater benefit for low 
SES patients. As a US Food & Drug Administration (FDA)-approved drug, minocycline is 
inexpensive and safe, such that positive results from this study could be applied relatively 
rapidly in clinical practice. 

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2.1 
Colorectal Cancer and Oxaliplatin-based Chemotherapy
Overall survival for advanced CRC has improved in the past decade, most strikingly because of 
rapid advances in chemotherapeutic regimens combining 5-fluorouracil with the newer cytotoxic 
agents (eg, irinotecan, ox-aliplatin) and targeted therapies. Oxaliplatin, a third-generation 
platinum, is a key chemotherapeutic agent used in first and subsequent lines of therapy for 
metastatic CRC and also in adjuvant therapy for CRC (André et al., 2004; Goldberg et al., 2004). 
The median survival for patients with metastatic CRC has been extended to 2 years and beyond, 
such that metastatic CRC is no longer viewed as an acute illness associated with a rapidly 
progressive course and early demise, but rather as a chronic disease requiring a long-term 
approach to treatment. Hence, for a patient with surgically unresectable disease, palliative 
chemotherapy is provided for the lifespan of the patient. Treatment goals no longer involve the 
use of intensive chemotherapy to salvage a few additional months of life, but now focus on 
enhancing quality of life with limited symptom burden—the so-called continuum-of-care 
paradigm (Goldberg et al., 2007). 
2.2 
CIPN and Inflammation 
It has been reported that macrophage accumulation and activation in the dorsal root ganglia 
(DRG) of paclitaxel-treated rats contribute to the development of neuropathy. The DRG of the 
spinal cord are the primary locations of cisplatin damage in the central nervous system (Meijer et 
al., 1999; Rabik & Dolan, 2007). Ledeboer et al (2007) demonstrated that paclitaxel-induced 
neuropathic pain is associated with induction of TNF-a and IL-1b in the lumbar DRG. This 
suggests that macrophages are the potential sources of these pro-inflammatory cytokines that in 
turn sensitize primary sensory afferents and modify sensory input to the spinal dorsal horn to 
facilitate pain. Experimental studies have shown that glial cell inhibitors such as propentofylline, 
thalidomide, and minocycline (selective for microglia) attenuate paclitaxel/vincristine-induced 
neuropathic pain (Cata et al., 2006; Sweitzer et al., 2006), further supporting a role for activated 
microglial cells in CIPN. 
2.3 
Socioeconomic Status and Activation of Innate Inflammatory Pathways 
Disparities in treatment and SES largely explained reduced survival among CRC patients who 
were African-American and had low SES (Le et al., 2008). Independent of personal income or 
educational attainment, adults living in less-advantaged neighborhoods exhibit higher levels of 
circulating proinflammatory markers than do residents of more-affluent areas. This association 
helps explain the increased risk of atherosclerotic cardiovascular morbidity and mortality 
conferred by low community-level SES (Petersen et al., 2008). The large population-based 
MIDUS study (Friedman & Herd, 2010) also suggested a link between social position and 
inflammatory markers of illness in the United States. After adjustment for demographic factors, 
health status, and health behaviors, those in the lowest quintile of pretax household-adjusted 
income or with less-than-high-school education had significantly higher levels of the 
inflammatory marker IL-6, the acute-phase response protein C-reactive protein (CRP), and 
fibrinogen. 

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2.4 
Disparity in Symptom Burden
We have previously documented that patients with advanced NSCLC treated at LBJ Hospital 
reported a significantly more-severe symptom burden than patients treated at MD Anderson with 
the same standard chemotherapy (Figure 1) (Cleeland et al., 2011). The most-severe symptoms 
were pain, fatigue, disturbed sleep, shortness of breath, drowsiness, and coughing; 30% of 
patients were in the high-symptom group. Lower education (OR=2.6 (1.3-5.2), p=.01) and 
non-white ethnicity (OR=2.8 (1.4-5.4), p=.002) were significant predictors of membership in the 
high-symptom group. We also found significantly more severe numbness/tingling (CIPN 
symptoms) in underserved patients (p=.018; unpublished data). This NSCLC symptom study 
provides a rationale for studying CIPN disparities in CRC patients seen at public versus 
private/academic hospitals (as proposed herein) and demonstrates the established research 
collaboration between MD Anderson and LBJ. MD Anderson faculty provide standard oncology 
care at each of these treatment sites. 
Patient-reported symptom outcomes raise a further research question regarding inflammatory 
mechanisms underlying high symptom burden and toxicity in low-SES patients undergoing 
standard therapy. In this study, we will investigate the quantitative relationship between 
inflammatory markers and neurotoxicity, as well as the potential differential effect of an 
anti-inflammatory and neuroprotective agent in patients seen in a private/academic center versus 
a public hospital.     

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2.5 
Symptom Profiles of Patients with CRC Undergoing Oxaliplatin-Based 
Chemotherapy In a recently completed prospective study of patients with CRC (MD Anderson 
protocol 2007-0637; PI: XS Wang), symptoms were documented in 100 patients for 12 months 
after the start of oxaliplatin-based chemotherapy, using the M. D. Anderson Symptom Inventory 
(MDASI). This study established collaborations between the Departments of Symptom Research 
and GI Medical Oncology at MD Anderson, demonstrated the feasibility of enrollment and data 
gathering for CRC patients, provided pilot-tested statistical methods for analyzing the symptom 
data, and provided a longitudinal symptom profile of neuropathy (numbness/tingling) during 
oxaliplatin-based chemotherapy. 
The Loess curves (Figure 2) show trends in symptom development in CRC patients over 12 
months. Numbness/tingling increased much more rapidly in severity and remained most severe 
after chemotherapy. In contrast, pain severity remained low during the first 3 months of 
chemotherapy and increased thereafter. Fatigue was the second-most-severe symptom during the 
study. Further, case-cluster trajectory analysis of symptom severity confirmed the clinical 
impression that not all patients suffered from high symptoms. On the basis of repeated symptom 
data and a 3-group cluster analysis of numbness data, 20% of patients had the highest severity, 
50% had rapid increase in severity in response to chemotherapy, and 30% reported low severity 
over 12 months. 
We collected serum samples and MDASI symptom ratings from 31 of the 100 patients with CRC 
(n=175 observations) and tested a panel of markers (IL-1RA, CRP, MCP-1, IL-6, IL-6R, TNF-á, 
sTNF-R1, sTNF-R2) (Wang et al., 2011). Mixed modeling, controlled for age, sex, cancer stage, 
number of chemotherapy cycles received, and body mass index (BMI), showed an association 
between inflammatory cytokines and the development of symptom burden. sTNF-R1 and IL-6 
were significantly and positively associated with the severity of the component score of the five 
most severe symptoms (fatigue, distress, drowsiness, disturbed sleep, and poor appetite). 
sTNF-R2 was associated with pain, and increased IL-6 was associated with the development of 
numbness/tingling (most relevant for this study).
We observed significantly more severe neuropathy in patients with NSCLC treated at the public 

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hospital (2.76 vs. 1.29 for mean numbness, effect size=0.515, p<.001). Figure 3 presents the 
average numbness severity from both groups (upper green line=LBJ). This unpublished CIPN 
result is consistent with the disparity in symptom burden for many other symptoms, which we 
reported in 2011 (Cleeland et al., 2011). 
2.6 
Symptom Intervention Agent: Minocycline 
2.61 
Anti-inflammatory Effects
Conceptually, modulation of treatment-induced immune dysregulation presents a 
potential mechanism for reducing treatment-induced symptoms (Hannestad et al., 2011; Miller, 
2003; Wang et al., 2010; Wood et al., 2006). Minocycline has broad anti-inflammatory and 
antioxidant properties, even though it is most often used as a synthetic antibiotic (Mishra & 
Basu, 2008). The anti-inflammatory effect of minocycline is manifest in both the peripheral and 
central nervous systems. In the former, minocycline has been proposed to treat rheumatoid 
arthritis and inflammatory bowel disease, although it is less effective than cytokine antagonists. 
At the level of the central nervous system, minocycline readily enters the brain because of its 
lipophilic properties (Aronson, 1980). It potently downregulates activated microglia, the 
inflammatory products of which lead to symptoms. The anti-inflammatory effects of minocycline 
and other tetracycline derivatives may be attributable to PARP-1 inhibition (Alano et al., 2006). 
Among other consequences, minocycline-induced inhibition of PARP-1 probably leads to the 
inhibition of p38 MAPK activation that has been observed in microglia exposed to minocycline 
(Sapadin & Fleischmajer, 2006; Tikka et al., 2001). In the context of our current studies on the 
pivotal role of inflammation in cancer-related symptoms, the downregulation of inflammatory 
signaling pathways by minocycline is the primary reason for selecting this drug for symptom 
prevention clinical trials. 
As we gain more understanding of cytokine networks, we may move away from single, 
well-defined pathways of inflammation toward a cytokine-targeting therapeutic strategy that 
blocks upstream cytokines with fewer side effects (Kopf et al., 2010). Minocycline could 
potentially provide this modulation. 

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2.62
Neuroprotective Effects
Animal studies have shown that minocycline abrogates the brain cytokine response to 
systemic lipopolysaccharide (LPS) and the development of LPS-induced sickness and depression 
(O'Connor et al., 2009). This effect, along with the inhibition of microglial activation caused by 
nerve damage, explains the neuroprotective action of minocycline that is observed in animal 
models of a number of diseases, including stroke, diabetic retinopathy, multiple sclerosis, and 
Parkinson disease. Minocycline prevents neuropathic pain (Padi & Kulkarni, 2008; Raghavendra 
et al., 2003). Minocycline prevented LPS-induced microglia/macrophage activation and cytokine 
responses in spinal cord and dorsal root ganglia, but did not affect the activation of astrocytes or 
satellite cells (Yoon et al., 2012). 
Dr. Patrick Dougherty’s group at MD Anderson has published other studies suggesting 
that minocycline’s profound immunomodulatory actions may provide a treatment option for the 
prevention or reversal of chemotherapy-related pain (Cata et al., 2008) and prevent 
taxane-induced hyperalgesia (Boyette-Davis et al., 2011). Minocycline effectively prevents the 
loss of intraepidermal nerve fiber density in oxaliplatin-treated rats (Boyette-Davis & 
Dougherty, 2011). Minocycline is also active in neurodegenerative disorders (Noble et al., 
2009), and HIV (Zink et al., 2005). Our colleagues’ results directly support our proposal that 
early mechanistic intervention might reduce numbness symptoms in patients with CRC receiving 
oxaliplatin-based chemotherapy. The clinical neurotoxicity produced by both chemotherapy 
agents is consistent; furthermore, observation of the preclinical effects of minocycline on CIPN 
supports the validity of translating the science from bench to bedside in this proposed study. 
2.63 
Anticancer Effects 
The tetracycline family includes tetracycline, doxycycline, and minocycline. The potent 
matrix metalloproteinase (MMP)-inhibitory activities of tetracyclines (especially their 
chemically modified analogs), combined with their relatively well-tolerated pharmacological 
profile, led several researchers to investigate their anticancer potential in a variety of cancers, 
including melanoma and lung, breast, and prostate cancers. Tumors from rats treated with 
chemically modified nonantibiotic tetracyclines (CMT-3) demonstrated reduced angiogenesis 
and increased apoptosis; both emerged as mechanisms of CMT-3 action (Lokeshwar, 2011). 
MMPs are important mediators of metastasis formation in the bone, contributing largely to the 
morbidity of patients with breast or prostate cancer. The natural osteotropism of tetracyclines 
would allow them to be highly effective in the inhibition of MMPs produced by osteoclasts or 
tumor cells in the bone. This hypothesis has now been confirmed by experimental evidence 
showing that doxycycline reduces tumor burden in a mouse model of breast cancer-derived 
osteolytic bone metastasis. This effect is likely due to a combination of multiple roles of 
doxycycline, including MMP inhibition and a negative effect on osteoclast differentiation and 
survival (Saikali & Singh, 2003). 
Minocycline inhibits cell proliferation and colony formation and downregulates cyclins 
A, B, and E, leading to arrest of cells in the G0 phase of the cell cycle and suppression of DNA 
synthesis. Furthermore, minocycline causes DNA laddering, activation of caspase-3, and 
cleavage of PARP-1. In nude mice bearing subcutaneous tumors, minocycline suppressed tumor 
proliferation index, angiogenesis, and tumor growth. This provided the initial basis for further 
evaluation of minocycline in the treatment of ovarian cancer (Pourgholami et al., 2012) and a 
potential role for minocycline in suppressing IL-6 expression and activity (Ataie-Kachoie et al., 

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2013), and supports the use of this agent in cancer patients.
2.64 
Safety
Minocycline has been used safely in thousands of patients over many years to treat a 
variety of clinical indications. It has a very low toxicity in preclinical studies and a sufficient 
safety profile as demonstrated in many studies of long-term use in humans. Common side effects 
of minocycline include light-headedness, vestibular symptoms, and nausea (Gump et al., 1977), 
without a correlation between serum concentration and toxicity. Minocycline was suspected in 
less than 2.5% of all common adverse events reported to the FDA (
http://www.drugcite.com/?q=minocycline). 
Minocycline has been used safely in CRC patients. A randomized double-blind, 
placebo-controlled trial (Scope et al., 2007) reported the usefulness of prophylactic oral 
minocycline in reducing acneiform rash in initial cetuximab treatment in CRC patients. 
Minocycline’s long-lasting effects in preventing neuropathic pain (Padi & Kulkarni, 2008; 
Raghavendra et al., 2003) and its potential role as a remedy for human inflammatory bowel 
disease (Huang et al., 2009), neurodegenerative disorders (Noble et al., 2009), and HIV (Zink et 
al., 2005) have been reported. Minocycline was safe and effective for patients with rheumatoid 
arthritis in a 48-week double-blind, placebo-controlled trial (Tilley et al., 1995). In clinical trials 
of minocycline for Fragile X Syndrome (Paribello et al., 2010), vitiligo (Parsad & Kanwar, 
2010), and schizophrenia (where it was used to block nitric oxide-induced neurotoxicity) 
(Levkovitz et al., 2010), the agent showed significant benefit and was well-tolerated. 
3.0 Background Drug Information
Minocycline hydrochloride (Minocin®, manufactured by Triax Pharmaceuticals, LLC, Cranford 
NJ) is a semisynthetic antibiotic derived from tetracycline. It has the unusual side effect of 
markedly suppressing proinflammatory cytokine release, the primary reason we will include it as 
an intervention in this study (Appendix C). Preclinical data suggests that minocycline reduces 
neural inflammation and prevents apoptosis of neural cells. Animal studies have demonstrated 
that minocycline reduces the levels of the proinflammatory cytokines IL-6, TNF-a, IL-b and 
interferon (IFN)-g (Ledeboer et al., 2005; Zanjani et al., 2006). Minocycline’s anti-inflammatory 
effect prevents subacute pathological change in lungs due to inflammation produced by 
peripheral LPS administration in animals (Yamaki et al., 1998). Minocycline was found to 
decrease IL-6 and CRP levels in patients with rheumatoid arthritis (Kloppenburg et al., 1996). 
3.1 
Minocycline Common Adverse Reactions 
Published FDA data show a very low incidence (< 2.34%) of minocycline-related side effects, 
including pyrexia (fever), rash, arthralgia, light-headedness, and nausea (
http://www.drugcite.com/?q=minocycline). Commonly associated side effects of minocycline 
include light-headedness, vestibular symptoms (such as dizziness and vertigo), headache, and 
nausea (Case, 2001; Gump et al., 1977), with no correlation seen between serum concentration 
and toxicity (Kloppenburg et al., 1995). Another side effect is photosensitization. Other adverse 
effects reported include serum sickness-like reactions, ototoxicity, azotemia, pulmonary infiltrate 
formation with associated eosinophilia, and discoloration of the sclera or teeth. A rare but serious 
reported side effect is pseudotumor cerebri.

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3.2 
Absolute Contraindications to Study Symptom Intervention Agent Minocycline
3.21
Hypersensitivity to any tetracycline
3.22 
Pregnancy
3.23
Hepatotoxicity (aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT)
3.3 
Minocycline Clinical Pharmacology 
3.31
Metabolism
Minocycline is metabolized to a significant degree; however, the nature of the metabolic 
products or sites of metabolism has not been elucidated with certainty (Allen, 1976).
3.32
Pharmacokinetics
Minocycline has a long serum half-life and can be administered at 12-hour intervals.
3.33
Time to Peak Concentration
Oral: 1 to 4 hours (Prod Info Dynacin®, 2011); (Prod Info Minocin®, 2008) (Macdonald 
et al., 1973; Simon et al., 1976). 
ꞏ
One to four hours after a single dose of two 100-mg minocycline capsules was given 
to 18 healthy fasting adults, the Cmax ranged from 2.1 to 5.1 micrograms per 
milliliter (mcg/mL) (Prod Info Minocin®, 2008) (Simon et al., 1976)
ꞏ
One hour after a single dose of two 100-mg minocycline capsules was given to 10 
normal adult volunteers, the Cmax ranged from 0.74 mcg/mL to 4.45 mcg/mL (Prod 
Info Minocin®, 2008)
3.4 
Minocycline Monitoring Parameters 
3.41 
Minocycline: LFTs, BUN, Sr Cr   
3.42 
Signs of acute hepatitis: rash, fever, malaise, abdominal pain, and vomiting 
Evidence: Hepatotoxicity (e.g., elevated hepatic enzymes, hyperbilirubinemia, hepatic 
cholestasis, hepatic failure with some fatalities, hepatitis with autoimmune features, and 
jaundice) has also been reported. Abdominal complaints may suggest hepatotoxicity; the 
incidence of this effect is roughly 4.7%. Liver toxicity is possible with excessive 
accumulation of the drug, which can occur in patients with renal impairment receiving 
even usual oral or parenteral doses. 
3.5
Minocycline Drug Interactions 
3.51
Antacids containing calcium, magnesium, or aluminum, bile acid sequestrants, 
bismuth, oral contraceptives, iron, zinc, sodium bicarbonate, penicillins, and quinapril may 
decrease absorption of minocycline; avoid taking within 2 hours of using this medication. 
3.52 
Methoxyflurane anesthesia: when concurrent with minocycline, may cause fatal 
nephrotoxicity. 
3.53 
Retinoic acid derivatives: may increase risk of pseudotumor cerebri. 

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3.54 
Warfarin: anticoagulant response may be increased with tetracyclines; monitor 
INR closely during initiation or discontinuation.
3.6 
Storage Information 
Store at 20°C to 25°C (68°F to 77°F).
*References for intervention agent: 
1.
MD Anderson Cancer Center Formulary: 
http://www.crlonline.com/crlsql/servlet/crlonline 
2.
Micromedex – Healthcare Series: http://www.thomsonhc.com/home/dispatch 
3.
Micromedex: Minocycline Drugdex Drug Evaluation and Armodafinil Drugdex Drug 
Evaluation and Turmeric Drug Evaluation by Martindale. 
4.
Lexi-Comp: Minocycline 
5.
Clinical Pharmacology: Minocycline 
3.7 
Serious Adverse Events for Minocycline 
No serious adverse events (SAEs) have been reported for this trial agent.
Other references include: 
1.
www.fda.gov, drug information
2.
National Committee for Clinical Laboratory Standards, Performance Standards for 
Antimicrobial Susceptibility Tests—Eighth Edition; Approved Standard. NCCLS Document 
M100-S8, Vol.18, No.1, NCCLS, 940 West Valley Road, Suite 1400, Wayne PA, January 1998. 
3.
http://www.drugs.com/pro/minocycline.html
4.0 Study Design
The primary objective of the proposed clinical trial is to examine whether minocycline, an 
anti-inflammatory agent shown to modulate the inflammatory pathway and biomarkers, will 
reduce or prevent cumulative oxaliplatin-induced peripheral neuropathy in patients with CRC, 
compared with placebo. A secondary objective is to examine the impact of mechanism-driven 
intervention with minocycline on levels of inflammatory markers (especially in low-SES patients 
with CRC). A translational agenda that includes a T-cell cellular cytokine assay will improve our 
understanding of inflammatory mechanisms. 
Design: Phase II randomized, 2-arm, double-blind, placebo-controlled trial
Sample: Patients with a pathologically proven diagnosis of CRC (N=84 evaluable patients), 
qualifying for oxaliplatin-based chemotherapy and minocycline treatment. 
Stratification by socioeconomic status (SES): Patients will be stratified by recruitment site 
(MD Anderson or LBJ) as a proxy for SES, which is typically determined via received education 
(years) and self-reported income (Friedman & Herd, 2010). For this study, we will verify low 
SES as the lowest quintile of pretax household-adjusted income and less than high school 
education (Gallo et al., 2005). Our assumption is that patients at LBJ are primarily low SES and 

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patients at MD Anderson are not low SES. 
Intervention Agent: Minocycline, 100 mg twice a day 
Study Period: Six months. Symptom intervention by minocycline/placebo throughout 4 months 
of oxaliplatin-based chemotherapy; symptoms will be reassessed at the 2-month follow-up visit, 
for a total trial period of 6 months per patient. Assuming that patients accrue at a rate of 3-4 
per month, we anticipate completion of recruitment in 40 months. 
The rationale for the 4-month intervention period is: (a) patients receiving a minimum dosage of 
oxaliplatin chemotherapy would be expected to reach a cumulative oxaliplatin dose (780 mg/m2) 
sufficient for development of peripheral neuropathy within 4 months; (b) in our previous study, 
the symptom profile of painful neuropathy over 4 months (8 cycles) of oxaliplatin showed a clear 
dynamic change; (c) patients are likely to have a tumor evaluation after 8 cycles of an 
oxaliplatin-based regimen; (d) considering that median progression-free survival (PFS) in stage 
IV CRC is about 10-12 months, a 4-month assessment timeframe will avoid any worsening of 
disease-driven symptom burden before progression in these patients. In sum, for this Phase II 
study that aims to demonstrate the principle, 4 months is a sufficient and appropriate time frame 
to observe the modulating effect of minocycline on peripheral neuropathy (primary outcome). 
Primary Outcome Variable: Area under the curve (AUC) for peripheral neuropathy (the 
“numbness/tingling” item from the MDASI gastrointestinal module [MDASI-GI]) over 4 
months. 
Schema:
5.0 Patient Eligibility
5.1
Inclusion Criteria 
5.11 
Patients with a pathologically proven diagnosis of CRC seen either at MD 
Anderson or LBJ.
5.12 
Patients > 18 years old. 
5.13 
Patients who qualify for oxaliplatin-based chemotherapy (in the adjuvant or 
metastatic setting) and are likely to receive at least 3 months of oxaliplatin.
5.14 
Patients who speak English or Spanish (due to language options for the MDASI 

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version being used in this study, we are only recruiting English-speaking or Spanish-speaking 
patients). 
5.15 
Patients with an NCI-CTCv4 sensory neuropathy score of 0 (Appendix D). 
5.16 
Patients with adequate renal function (serum creatinine must be < 1.5 times the 
upper limit of the institutional normal range) and no prior renal disease that in the opinion of the 
attending physician would make the patient ineligible to receive the study drug. Test results must 
be no more than 3 months old.
5.17
Patients with adequate hepatic function (total bilirubin must be < 2.0 times the 
upper limit of the institutional normal range; alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) must be < 3.0 times the upper limit of the institutional normal range). 
Test results must be no more than 3 months old. 
5.18 
Patients willing and able to review, understand, and provide written consent. 
5.2
Exclusion Criteria  
5.21 
Patients continuously taking any minocycline within the last 15 days. Patients 
who have conditions that potentially preclude use of minocycline as determined by the treating 
physician. 
5.22
Patients continuously taking systemic steroids within the last 15 days.
5.23
Patients with autoimmune disorders (for example, systemic lupus erythematosus 
or rheumatoid arthritis), who have been treated in the last 3 years. 
5.24 
Patients who are pregnant; the absence of pregnancy will be confirmed by 
negative urine test.
5.25 
Hypersensitivity to any tetracyclines, or a history of other allergies or drug 
reactions that in the treating physician's judgment make the patient inappropriate for this study.
5.26 
Patients receiving vitamin K antagonist (warfarin). 
5.27 
Patients with a BMI >40 (Obese Class III criteria)
5.28
Patients who will receive cetuximab or other targeted therapy where physicians 
may use topical doxycycline to reduce the rash associated with therapy. 
6.0 Patient Enrollment and Registration
6.1 
Patient Enrollment 
The proposed clinical trial will be conducted by the Department of Symptom Research in 
collaboration with the GI Medical Oncology and General Oncology departments at MD 
Anderson. Dr. Cathy Eng will serve as the protocol PI and Dr. Nishin Bhadkamkar will serve as 
site PI at LBJ. 
Patients will be screened for eligibility and recruited for enrollment in the GI Medical Oncology 
clinics at MD Anderson and the Medical Oncology clinic at LBJ before their chemotherapy 
starts. Research staff will maintain a log of all patients screened; the reasons that patients do not 
enter the study will be documented. Patients who agree to enroll in the study will provide written 

2013-0323
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informed consent. 
At enrollment, patients will be informed that they will receive a stipend in the total amount of 
$60 for participation in the study. The stipend will be distributed in $20 increments three times 
during the study. Stipends will be distributed to participants after completion of MDASI-GI at 
baseline, and at the end of months 4 and 6 of chemotherapy treatment.
All enrolled patients will be registered into the MD Anderson Clinical Oncology Research 
System (CORe).  
6.2 
Patient Randomization and Assignment to Treatment Arm 
In order to reach our targeted number of evaluable patients, the study will accrue up to166 
patients (83 patients each in the placebo and minocycline groups). A randomization list will be 
generated by our biostatistician collaborator from the Department of Biostatistics for all 166 
patients; it will state the group to which each patient will be randomized. This list containing the 
accrual number and treatment group information will be set up in the Clinical Trial Conduct 
website. Study staff will be blinded to randomization arm.
After a patient is enrolled, the Investigational Pharmacy will retrieve the randomized treatment 
arm information from the Clinical Trial Conduct website. Once a patient is randomized to a 
treatment arm, Investigational Pharmacy will relay the information to the dispensing Pharmacy.
6.3 
Pretreatment Evaluation 
In order for study staff to determine patient eligibility, patients must have had the following tests 
prior to initiating chemotherapy and the study trial agent. These tests will be completed by their 
treating physician, as part of their standard prechemotherapy evaluation.
6.31 
Blood chemistries (albumin, creatinine, SGOT, total bilirubin, ALT, and AST) 
and complete blood count (WBC, Hgb, platelets) will be reviewed; we will also document other 
lab data if available in the patient medical records (Appendix E).
6.32
Pregnancy test, if the patient is a female of childbearing potential.
6.33
History and physical examination (including documentation of current 
medications and Eastern Cooperative Oncology Group performance status (ECOG PS).

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7.0 Administration of Pharmacological Agent 
Preparation and dispensing of intervention medication (minocycline or placebo) for each patient 
will be coordinated by the investigational pharmacies at MD Anderson and LBJ. The study 
medication will be compounded at the GreenPark pharmacy, which has done this same 
minocycline/placebo compounding for several of our other studies. Matching capsules for placebo and 
minocycline will be compounded. The presentation will be a 100-mg capsule containing a powder. 
Patients will pick up the assigned study medications at one of the outpatient pharmacy stations at 
MD Anderson or the pharmacy at LBJ, or study medication will be mailed to the patient by the MD 
Anderson pharmacy. Patients will be given instructions on the study medication, and the study 
research staff will provide a Minocycline Patient Education Leaflet on how to take the drug and 
its interactions (Appendices W and X). Administration of minocycline for patients randomized to 
receive it will be 200 mg/day, an effective dose used safely for up to 18 months in other studies 
(Case, 2001). 
Information on potential contraindications and interactions appears in Section 3.0, Background 
Drug Information. The interaction screening will be the responsibility of the dispensing 
Pharmacy. Research staff will review all medications being taken by the patient prior to 
initiating treatment. During the intervention, the research staff will capture all drug interactions 
causing an adverse event on the Adverse Event form. We plan to document important symptom 
control medications that patients will be or have been using during the trial. Minocycline will 
begin at the start of chemotherapy and continue daily through the 4-month intervention period. 
The participants will take study medication twice daily, including weekend days, starting on day 
one of chemotherapy. The table below displays the symptom intervention agent and the dosing 
schedule (Lexi-Comp). 
Symptom 
Intervention Agent
Dosage Form
Initial Intervention Dose 
(first day of 
chemotherapy)
Initial Placebo Dose 
(first day of 
chemotherapy)
Minocycline
100-mg capsules
100 mg two times a day (200 
mg)
Matching placebo
Study staff will contact patients every cycle to check for adverse events (either during routinely 
scheduled clinic visits or via telephone calls).
Patients will be asked to bring their study medication container to the clinic at each 
chemotherapy cycle start so that study staff can perform a capsule count during a scheduled 
appointment. Unused drugs will be returned to the investigational pharmacy by the study staff. 
Study staff will contact patients every cycle to check medication use (either during routinely 
scheduled clinic visits or via telephone calls). 
Patients and family members will be asked to notify the research team if the patient is 
hospitalized or moves to another location. Patients hospitalized because of complications will be 
identified and tracked by the research coordinator. Tracking of patient hospital admissions will 
be conducted either through (1) checking admissions through the institutional database; (2) 
contacting the closest relative; (3) and/or follow-up with the outpatient clinic nurse in the clinic. 
The reason for hospital admission will be recorded. When a family member or health care 
provider notifies the research coordinator of the death of a patient, the date of death will be 
recorded.

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8.0 Data Collection 
8.1 
Patient-Reported Outcome (PRO) Measures 
8.11 
Symptom Measurement (Appendix F)
The MDASI is a multiple-symptom measure of the severity of cancer-related symptoms 
and the functional interference caused by symptoms that is sensitive to disease and treatment 
changes (Cleeland et al., 2000). This instrument is brief, easily understood, and validated in the 
cancer population. Patients rate the severity of 13 physical, affective, and cognitive symptoms on 
0–10 numeric scales, ranging from “not present” to “as bad as you can imagine.” The MDASI 
also assesses 6 items related to symptom interference with functioning, also on a 0–10 numeric 
scale ranging from “did not interfere” to “interfered completely.” 
For this study, symptom data will be collected using the gastrointestinal module of the 
MDASI (MDASI-GI). The MDASI-GI includes the 13 symptoms and 6 interference items from 
the core MDASI, along with 5 additional symptoms known to be important in assessing patients 
with CRC (constipation, diarrhea/watery stools, difficulty swallowing, change in taste, and 
feeling bloated). The MDASI-GI takes less than five minutes to complete. MDASI-GI items will 
be used to calculate the symptom AUC.
We will collect MDASI-GI assessments weekly. We will use paper or a secure electronic 
method when the patient is in the clinic, and use an interactive voice response (IVR) system, 
phone calls by field coordinators, secure web access, or regular mail when patients are away 
from the clinic. The method of collecting the MDASI-GI assessments weekly will be based on 
patient preference and may be varied throughout the study based on patient request. See Section 
8.5.
The IVR System. An IVR system can greatly facilitate the longitudinal tracking of symptoms in 
patients. IVR systems are programmed to call patients at home for symptom assessment. The 
IVR system asks patients to rate each symptom and interference item on the MDASI-GI’s 0–10 
numeric scales using the keypad of a touchtone telephone. 
Participants electing to use the IVR system may be provided with an informational 
brochure outlining the steps to complete an IVR call (Appendix G). A telephone number will be 
provided in the event of questions or problems. Patients will also be given a Patient 
Identification Number (PIN) for access to the system. IVR calls will be scheduled at a time that 
is convenient for the patient. 
Completion or failure of calls will be monitored by the research staff. In the event of 
missed calls, a notification screen will appear in the IVR system to alert the research staff. The 
research staff will then contact the patient, check on their status and, if possible, complete the 
assessment with the patient during the telephone interview. The system will continue calling the 
patient at the preset schedule.
The IVR symptom and interference data will be available on an MD Anderson intranet 
site with access limited to authorized project staff only. Patient data will be identified by subject 
study number.

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8.12
Measure of Quality of Life (Appendix H)
The EuroQol (EQ-5D) is a standardized instrument for use as a measure of health 
outcome. Applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status. The EQ-5D was originally designed 
to complement other instruments but is now increasingly used as a stand-alone measure. The 
EQ-5D descriptive system consists of 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has three levels, reflecting "no health 
problems" (level 1), "moderate health problems" (level 2), and "extreme health problems" (level 
3). A dimension for which there are no problems is said to be at level 1, while a dimension for 
which there are extreme problems is said to be at level 3. Each unique health state described by 
the instrument has an associated 5-digit descriptor ranging from 11111 for perfect health to 
33333 for the worst possible state. The resulting descriptive system defines 243 health states. In 
addition, "unconscious" and "immediate death" are included in the EQ-5D valuation process but 
are not a part of the descriptive system. We will collect this data at baseline, end of symptom 
intervention and end of the trial. 
Reporting Requirement
If in the course of assessing symptoms the patient reports severe levels of sadness (7 or 
above on the MDASI-GI) or extreme anxiety or depression (" I am extremely anxious or 
depressed" on the EQ-5D), the clinical data coordinator will notify the patient's treating 
physician immediately to make him/her aware of the patient's condition.
Patients using the IVR system when away from the clinic will be instructed by the 
research team to report severe symptoms to their physician or go to the emergency room. The 
research staff will notify the clinical service should patients report a high symptom-severity 
level. These patients will receive standard care at MD Anderson or LBJ. 
8.13 
Measures of Chemotherapy-Induced Peripheral Neuropathy (Appendices I 
and J)
The Chemotherapy-Induced Neuropathy Assessment Scale (CINAS) is a newly 
developed tool that asks patients to rate their neuropathy during the last 24 hours on a 0–10 scale 
(Thomas et al., 2012). The severity of sensory and motor neuropathy will be assessed with the 
EORTC QLQ-CIPN-20. The sensory neuropathy subscale includes the cumulative score for nine 
questions that assess sensory toxicities, with total scores ranging from 0 to 36. The motor 
neuropathy subscale includes the cumulative score for seven questions that assess motor 
toxicities, with total scores ranging from 0 to 28. The sensory neuropathy subscale includes 
questions about tingling, numbness, and burning pain in the hands or feet and problems standing 
or walking because of an inability to feel the ground beneath one’s feet. The motor subscale asks 
questions about cramps in the hands and feet, difficulty holding a pen, difficulty manipulating 
small objects, difficulty opening a jar or bottle because of weakness in one’s hands, difficulty 
walking because one’s feet dropped downwards, and difficulty climbing stairs or getting out of a 
chair because of weakness in one’s legs. The EORTC QLQ-CIPN 20 was shown in pretesting to 
have internal reliability with Cronbach alpha scores of 0.82 and 0.73 for the sensory and motor 
neuropathy subscores, respectively (Postma et al., 2005). The CINAS is available in English 
only.

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8.14 
Tobacco History Form (Appendix K) 
The Tobacco History Form is a short questionnaire that asks about smoking history. 
8.15 
Other Data to be Collected
The study coordinator will collect in RedCap demographic, disease, and treatment information 
from the medical record (if the information is available), such as but not limited to: birth date, 
gender, race, marital status, diagnosis, date of diagnosis, disease stage, past and current cancer 
treatment, BMI, symptom management, routine laboratory values, and comorbidities. The 
research coordinator  will assess the patient’s ECOG PS and maximum CTC toxicities scores 
and date for sensory and motor neuropathy and diarrhea in the last 7 days or since the last 
assessment, document these assessments, and record the data in RedCap. The coordinator will 
query the patient for education, employment status, yearly income, and number of people living 
in the patient’s home, document the patient’s answers, and record the data in RedCap. The 
research coordinator will query the patient as to number of doses of study medication the patient 
has taken and missed since the last assessment, note the number of pills dispensed from the 
patient’s pill bottle, and count the number of pills remaining in the bottle. This information will 
be documented and the data collected in RedCap. If the patient does not return the pill bottle, the 
information on number of pills dispensed and returned will not be documented or collected. 
When the patient goes off study, the research coordinator will document the reason and the date 
and record the data in RedCap. Assessments will be performed and data collected according to 
the schedule in 8.3.
8.2 
Objective Measure: Bumps Detection Test
Impairment in touch sensation was especially pronounced in patients with CRC when 
measured using the Bumps detection test (Boyette-Davis et al., 2012), which is a relatively new, 
objective measure of neuropathy (Kennedy et al., 2011). The Bumps test will be administered in 
the clinic by research staff. Patients use a fingertip to detect small particles (bumps) of varying 
height (bumps detection) on a smooth surface. The Bumps device consists of 3 etched glass 
plates (11.5 cm x 15 cm), each of which contains twelve 1.5 x 1.5 inch squares. Within each 
square, there are 5 flat circles, each of a different color. Located over one of the circles within 
each square is a bump that is 550 mm in diameter. Bumps on plate 1 vary from 2.5 to 8.0 mm in 
height, bumps on plate 2 vary from 8.5 to 14.0 mm in height, and bumps on plate 3 range from 
14.5 to 26 mm in height. Participants will be instructed to use the index finger of the dominant 
hand to explore the 5 circles within each square, beginning with the upper left square and 
moving from left to right and top to bottom. Patients will not able to see the location of the bump 
and must report to the examiner in which colored circle they perceive the bump.
8.3
Assessment Schedule 
Time point by chemotherapy cycle
Baseline
Pre MIN 
Tx
1
Every 3 to 4
 weeks
8
~1m 
(at 
clinic 
visit)
2
~2m 
(at 
clinic 
visit)
2
~3m 
(at 
clinic 
visit)
2
End of 
MIN Tx 
(~4m)
End of 
trial 
(~6m)
3
On-study
X

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Charlson Comorbidity Index
X
Demographic 
X
Clinical Monitoring
X
X
X
X
Laboratory Data 
X
X
X
X
X
Study Medication Accountability
4
X
X
X
X
X
CTC Toxicity
X
X
X
X
Final Study Status
X
MDASI-GI 
4, 5
X
X
X
X
X
EQ-5D 
4
X
X
X
CINAS
4, 6, EORTC CIPN-20
4
X
X
X
X
X
Tobacco History
4
X
X
Bumps test and research blood draw for 
markers
7
X
X
X
X
1. Baseline: within 3 weeks before the first dose of chemotherapy is administered.
2. At the chemotherapy cycle closest to the time point.
3. End of trial: completion of 6-month study or upon patient withdrawal.
4. Patient-dependent forms will be completed if the patient can be contacted and is willing and able to 
complete.
5. The MDASI-GI will be completed weekly.
6. The CINAS will be administered to English-speaking patients only.
7. Blood for biomarkers will be collected if possible. The Bumps test will be administered when possible 
at Harris Health LBJ Hospital. 
8. Assessments may be completed within +/- three days.
8.4 
Blood Sample Collection for Inflammation Marker Testing
We will sample blood for testing of serum cytokines/chemokines and T-cell mitogen-induced 
cytokine/chemokine production using CD3/CD28 antibodies. Monocyte cytokines/chemokines 
will be induced by in vitro stimulation with LPS. We will concurrently track biomarkers of 
inflammation at baseline, 2 months, 4 months (end of intervention), and at the end of the trial at 
6 months. For patients undergoing surgery, we will not collect blood for the first 4 weeks after 
surgery.
Blood (10 mL) for amino acids and amino acid metabolytes will be collected into ethylene 
diamine tetra acetic acid (EDTA) tubes and kept on ice; 10 mL of blood will be collected in a 
tube containing Na-heparin and kept at room temperature; and 10 mL of blood for serum 

2013-0323
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Page 20
inflammatory markers will be collected and kept on ice. Heparinized blood will be diluted 1/10 
with culture medium in the presence of either CD3/CD28 antibodies or LPS. 18 hours after LPS 
stimulation or 72 h after T cell mitogen stimulation, culture supernatants will be collected and 
stored at –80C until batch-wise analysis of cytokine/chemokine profiles using multiplex 
technology. Cytokines and chemokines that will be measured are: IL-1, IL-1RA, IL-2, IL-4, 
IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, IFN-g, TNF-a, IP-10, MIF, MCP-1, sTNFRI and 
sTNFRII, sIL6R as described by us before (van Zuiden M, Heijnen CJ,  2011). Plasma levels of 
the downstream markers albumin, neopterin and CRP will be assessed as previously described 
(Capuron et al., 2011; Wang et al., 2008). Plasma levels of tryptophan, kynurenine, 
phenylalanine, and tyrosine will also be determined by HPLC to study their possible association 
with on the one hand cytokine/chemokine profiles and on the other hand with fatigue and mood 
changes will be assayed (Capuron et al., 2011). 
NF-kB analysis: NF-kB is a master transcriptional regulator of cytokine and chemokine 
production. We will test the activity of NF-kB by determining NF-kB activation after culturing 
whole blood for 3, 5 and 10 minutes with LPS or antiCD2/CD28 followed by FACS analysis 
using cellular activation kits consisting of labeled antibodies against NF-kB p50/p65 (Becton 
and Dickinson, USA). All the parameters have been extensively tested for validity and 
interindividual variation in our laboratory of Neuroimmunology of Cancer-Related Symptoms 
(NICRS).
Markers of inflammation are selected from among the effector components of the inflammatory 
response (cytokines and their soluble receptors). Circulating cytokines/chemokines to be 
measured include proinflammatory and anti-inflammatory cytokines and receptors (IL-1RA, 
IL-6, IL-8, sIL-6R, IL-10, MCP-1, sTNF-R1, and sTNF-R2). We will also test the 
kynurenine/tryptophan ratio that associated with increased plasma levels of neopterin, a marker 
of macrophage activation, which points to activation of the tryptophan-catabolizing enzyme 
IDO.
8.5 
Data Confidentiality Plan
All patient-reported outcome, laboratory, and clinical data gathered in this protocol will be 
stored in a password-protected database. All patient information will be handled using 
anonymous identifiers. Linkage to patient identity is only possible after accessing a 
password-protected database. Access to the database is only available to individuals directly 
involved in the study. Patient folders containing case report forms are kept in locked cabinets in 
the Department of Symptom Research.
Data is collected either (1) on scannable paper-and-pencil Teleforms that can be administered 
face-to-face in the clinic, through phone calls by field coordinators, or by regular mail, or (2) via 
Health Insurance Portability and Accountability Act (HIPAA)-compliant, institutionally 
approved, secure electronic data-capture methods (eg, tablet PCs in the clinic, the IVR system, or 
the web-based REDCap application hosted by MD Anderson). Electronic capture eliminates the 
need for hand data entry.  All data resides in a relational database with audit tracking for efficient 
data retrieval.  All data and software related to the patient data is password protected with 
controlled access.  
A custom software application performs protocol tracking, along with data management and 

2013-0323
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quality assurance for symptom outcome data. The software monitors patients as they progress 
through the protocol from screening to off-study and informs the data coordinators of protocol 
events and what case report forms to administer.  The protocol tracking software also tracks 
when patient data is collected, scanned, and monitored.  Routine data processing is made 
expeditious by simplifying the creation of custom algorithms and storing them for future use. 
These algorithms check the data for potentially erroneous values, and then automatically write 
them to an error log for later review. Data set review also consists of reviewing labels, value 
codes of the data, and logic checks. Should the data require correction, the changes are made to 
the data themselves, and the description of those changes is documented in the error log. The 
data management application also allows for easy dataset construction using several pre-loaded 
architectural paradigms. 
REDCap (Research Electronic Data Capture) electronic data capture tools (
www.project-redcap.org) is a secure, web-based application hosted at MD Anderson with 
controlled access designed to support data capture for research studies (Harris et al., 2009). 
REDCap provides: 1) an intuitive interface for validated data entry; 2) audit trails for tracking 
data manipulation and export procedures; 3) automated export procedures for seamless 
downloads to common statistical packages; and 4) procedures for importing data from external 
sources. In the case of multi-center studies REDCap uses Data Access Groups (DAGs) to ensure 
that personnel at each institution are blinded to the data from other institutions. REDCap (
https://redcap.mdanderson.org) is hosted on a secure server by MD Anderson’s Department of 
Research Information Systems & Technology Services. REDCap has undergone a Governance 
Risk & Compliance Assessment (05/14/14) by MD Anderson's Information Security Office and 
found to be compliant with HIPAA, Texas Administrative Codes 202-203, University of Texas 
Policy 165, federal regulations outlined in 21CFR Part 11, and MD Anderson’s Institutional 
Policy #ADM0335. Those having access to the data file include the study PI and research team 
personnel. Users are authenticated against MD Anderson's Active Directory system. External 
collaborators are given access to projects once approved by the project sponsor. The application 
is accessed through Secure Socket Layer (SSL). All protected health information (PHI) will be 
removed from the data when it is exported from REDCap for analysis. All dates for a given 
patient will be shifted by a randomly generated number between 0 and 364, thus preserving the 
distance between dates. Dates for each patient will be shifted by a different randomly generated 
number. After publication, study data will be archived in REDCap.
In addition, after all analysis has been completed and all study results have been reported, patient 
data will be permanently and securely stored in an institutional big data warehouse and made 
available to all research and clinical faculty, with appropriate validation and access controls, so it 
can facilitate research cross-fertilization and speed insight discovery.
9.0 Reporting Requirements
9.1 
Adverse Events (AE)  
Patients will be seen in the outpatient clinics for each chemotherapy cycle, allowing for close 
monitoring of potential adverse events (AEs) by clinic and research staff. Treatment-related 
toxicities (NCI Common Terminology Criteria for Adverse Events, version 4) will be monitored 
by both clinic and research staff at the patient’s regular clinical appointments or by phone call. 

2013-0323
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Grade 1 and Grade 2 AEs will not be reported. AEs that are Grade 3 and above are 
considered to be serious adverse events (SAEs) and will be reported. SAEs that are unexpected 
and related (definitely, probably, or possibly related) to the study medication will be reported 
promptly according to institutional policies (see Section 9.2 below). SAEs that are either (1) 
expected or (2) unexpected but unrelated (unrelated or unlikely to be related) to the study 
medication will be summarized on the continuing review report. The principal investigator and 
the treating physician will determine whether or not an AE is related to the study medication. 
When clinically indicated, all patients will receive standard supportive care, including but 
not limited to antiemetics, antibiotics, nutrition, and pain management. Patients will stop taking 
minocycline if grade 3 toxicity occurs.
A list of adverse events known to be associated with primary treatment is listed in section 
4.0 of the protocol. 
9.2 
Serious Adverse Events (SAE) 
9.21
Definition
A serious adverse event is any adverse drug experience occurring at any dose that results 
in any of the following outcomes: 
ꞏ
Death. 
ꞏ
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
ꞏ
Inpatient hospitalization or prolongation of existing hospitalization 
ꞏ
A persistent or significant disability/incapacity – a substantial disruption of a person’s 
ability to conduct normal life functions. 
ꞏ
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate 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. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room, convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
Important medical events as defined above may also be considered SAEs. Any important 
medical event can and should be reported as an SAE if deemed appropriate by the Principal 
Investigator or the Clinical Research Support Center.
9.22
Reporting Serious Adverse Events
It is the responsibility of the PI and the research team to ensure SAEs are reported 
according to the Code of Federal Regulations, Good Clinical Practices, protocol guidelines, the 

2013-0323
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sponsor's guidelines, and MD Anderson Institutional Review Board (IRB) policy.
All events occurring during the conduct of the protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas MD Anderson Cancer Center Institutional Review Board Policy on 
Reporting Serious Adverse Events.” Unless stated otherwise in the protocol, all SAEs, expected 
or unexpected, must be reported to the MD Anderson IRB within five working days of 
knowledge of the event, regardless of attribution. 
All life-threatening or fatal events, expected or unexpected, and regardless of 
attribution to the study drug, must be reported to the MD Anderson IRB in writing within 24 
hours (next working day) of knowledge of the event. 
Additionally, any SAEs that occur more than 30 days after the last dose of study drug 
that are related to the study treatment must be reported to the MD Anderson IRB Office. This 
may include the development of a secondary malignancy.
The MD Anderson “Internal SAE Report Form for Prompt Reporting” will be used for 
reporting to the MD Anderson IRB.
10.0 Unblinding 
In the event of an SAE (as defined above) or an emergency situation that is likely due to the 
symptom trial agents as determined by the treating physician or PI, the investigational pharmacy 
at either MD Anderson or LBJ, as appropriate, will be asked to unblind the symptom trial agents 
for the affected study subject. Pharmacy staff will proceed with unblinding and will contact the 
PI with the symptom trial agent information so that the treating clinicians can appropriately 
manage the SAE and confirm the specific source of the SAE. All incidents of unblinding will be 
documented by the study team and will also be maintained on file in the Investigational 
Pharmacy Services for reference. The Investigator must notify the MD Anderson IRB when 
unblinding occurs. 
11.0 Criteria for Removal from the Study  
11.1 
Development of an SAE related to the study drug.
11.2
Inability to comply with protocol requirements at baseline or within three months of 
study start is defined as an inevaluable case.
11.3
If it is determined that patient is unable to comply with protocol requirements 
(specifically study medication), or if treatment with oxaliplatin is discontinued after three 
months of study start, patient will remain on study for PRO data collection unless patient 
requests to be removed from study.
11.4
Pregnancy during the study period.
11.5
Any of these values are met or exceeded:
11.51 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3.0 times 
the upper limit of normal 

2013-0323
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11.52 Total bilirubin > 2.0 times the upper limit of normal
11.53 Signs and symptoms of severe rash (CTC > grade 3) and hypersensitivity; if these 
appear, the study drug must be stopped immediately and the patient must be removed 
from the study
11.54 INR > 1.5; treating physician notified so that medical management occurs
11.6
Completion of study.
12.0 Statistical Analysis Plan 
12.1 
Sample Size and Randomization
Patients will be randomized equally to the 2 arms (minocycline and placebo) and stratified by 
SES. We will use the treatment setting (MD Anderson versus LBJ) as the stratification variable, 
as LBJ is likely to enroll patients with low SES. A balanced randomization scheme using a 
random permuted block method will be implemented (see schema, Section 5.0). Study staff will 
be blinded to randomization arm.
The primary outcome variable is the AUC for numbness/tingling over ~4 months. The area under 
the curve (AUC) will be calculated using trapezoidal approximation. The base of a trapezoid 
corresponds to the number of days between assessments while the heights correspond to two 
adjoining symptom responses. The number of trapezoids depends on the number of symptom 
assessments. The sum of the area for all the trapezoids represents the AUC of a particular 
patient. Our preliminary data in CRC chemotherapy show that the average 4-month numbness 
AUC is 205.76 (equivalent to a mean daily AUC of 1.7), with a standard deviation of 168.3. 
With 42 evaluable patients per arm, we will be able to detect a difference of 103.5 (standardized 
difference of 0.61) on the symptom AUC between the 2 arms with 80% power and a 2-tailed 5% 
significance test. We will continue to accrue patients until we have reached the specified 
evaluable patients per arm. Because we expect that approximately 49% of the patients may 
become inevaluable, we will accrue up to 166 patients.
Patients who drop out of the study after entering three months of AUC data will be included by 
carrying their last symptom data forward for the remaining study period. If patients stop the 
study intervention after 3 months of trial, but continue to provide PRO data, this data will be 
included in the AUC analysis, instead of using the carryover method for missing timepoints.

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12.2 
Analysis Plan
12.21 Primary Outcome
Estimates of treatment effect will be obtained using standard linear regression techniques 
in which AUC values are regressed on indicator variables that represent treatment received. We 
will include the effect of SES status, prior oxaliplatin treatment, age, gender, BMI, and disease 
stage in the regression model. If the distribution of the outcome variables cannot reasonably be 
regarded as Gaussian, we will investigate transformations of both response and explanatory 
variables to a scale upon which a Gaussian model can be employed.  To assess the effect of 
patients who drop out of the study, we will use a selection model to account for informative 
dropouts and include the effect of SES status, prior oxaliplatin treatment, age, gender, BMI, and 
disease stage as well as those baseline characteristics that are unbalanced between the dropouts 
and completers as covariates in the model.  
In addition to the formal evaluation of treatment effects on the primary outcome, we will 
also examine the prognostic effects of baseline sensory deficit from the Bumps test (if available), 
tumor response, ECOG PS, comorbidity, and supportive-care agent used, if any, in predicting the 
outcome variable. Supplementary analysis will be performed by fitting linear mixed models with 
symptom scores as the dependent variable with time, treatment group, and other covariates as 
independent variables. 
An interim analysis will be performed after 50% of the targeted number of patients (84) 
are evaluable; that is, after 42 patients are evaluable. An evaluable patient is one who has 
contributed PRO data for at least three months of the trial period and whose 4-month AUC can 
be calculated. We propose that the trial be stopped if there is evidence that the numbness AUC 
between the minocycline and placebo arm is significantly different at p<.005. The test of the 
numbness AUC between the groups at the end of the trial will be tested at p<.048.   These 
critical values are based on the O’Brien-Fleming approach (O’Brien and Fleming, 1979) with 
two looks. 
12.22 Secondary Outcomes
12.221 To examine the clinical efficacy of minocycline in reducing fatigue during 
oxaliplatin-based chemotherapy in patients with CRC. We will examine the effect of 
minocycline on fatigue using the same approach under the primary outcome but with fatigue 
AUC instead of numbness/tingling AUC as dependent variable in a regression model consisting 
of an indicator variables that represent treatment received, SES status, prior oxaliplatin 
treatment, age, gender, body mass index and disease stage. 
12.222 To examine the effect of SES on the clinical efficacy of minocycline in reducing 
acute peripheral neuropathy during oxaliplatin-based chemotherapy in patients with CRC and to 
determine if the level of neuropathy remains the same after patients are taken off study 
medications. 
 To test the hypothesis that the benefit of minocycline is greater for patients with low 
SES, we will compute and compare the difference scores between placebo and minocycline 
within the low-SES and high-SES groups. We expect the difference scores for the low-SES 
group to be greater than the difference scores for the high-SES group. To determine if 
neuropathy level is stable after patients are off their study medications, we will calculate change 
in numbness/tingling from month 4 to month 6 (end of study period). We will test whether the 

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change scores are significantly different from zero. This finding will be interpreted with caution, 
as patients who remain on the study are likely to report lower or stable symptoms.
12.223 To examine the interaction between SES and inflammation (circulating cytokines 
and activation of immune cells) and the effect of this interaction upon symptom development in 
CRC patients. We will correlate neuropathy, numbness, and fatigue levels with reduction in 
expression of inflammatory markers (serum proinflammatory cytokines and T-cell cytokine 
release in response to ex vivo activation with a mitogen) within the low-SES and high-SES 
groups. We hypothesized that the reduction in inflammatory markers will be greater in low-SES 
patients.  
12.224 To explore the relationship between objective measures of neuropathy and fatigue 
and patient-reported symptom outcome measures and health status. If Bumps test results are 
available, we will compare differences between the CINAS and Bumps test results at baseline 
and end of trial and we will report the effect sizes of these change scores. We will use the EQ-5D 
dimensions as dependent variables to explore whether health status differs between patients 
treated with minocycline vs. placebo and to estimate these effects. 
As with any clinical trial, missing data and early withdrawal is a challenge. To address 
dropout related to the outcome, we will include a dropout variable in the mixed models and an 
interaction term with treatment groups to determine whether there is differential dropout between 
groups. We will also compare results from mixed models using (1) all available data and (2) data 
from only those patients who complete the entire study.
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