Conditions: Pancreatic Cancer
Keywords: Pancreatic Cancer Pancreatic adenocarcinoma Locally advanced Metastatic disease Symptom reduction Minocycline Dynacin Minocin Minocin PAC Myrac Solodyn Placebo Sugar Pill Questionnaires Surveys
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if minocycline can reduce the side effects of chemotherapy in patients with pancreatic cancer. In this study, minocycline will be compared to a placebo.

Minocycline is an antibiotic that may help to reduce side effects of chemotherapy.

A placebo is not a drug. It looks like the study drug, but it is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.

Detailed description:
Study Groups:

If you agree to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups. You will have an equal chance of being in either group:

* If you are in Group 1, you will take minocycline.
* If you are in Group 2, you will take a placebo.

Neither you nor the study staff will know if you are receiving the study drug or the placebo. However, if needed for your safety, the study staff will be able to find out what you are receiving.

Study Drug Administration:

Each study cycle is about 2 weeks.

You will begin taking the study drug/placebo on, or within 2 days of, Day 1 of the first chemotherapy cycle after you are enrolled on the study. You will take the study drug/placebo capsule by mouth, every day for up to 4 cycles (up to 8 weeks, if there are no treatment delays).

It is possible that your chemotherapy start may be delayed if it takes additional time for your central venous catheter (CVC) to be placed. A CVC is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. If this happens, you may choose to start taking the study drug/placebo up to 2 weeks before you start chemotherapy, instead of waiting to start taking it on the same day your chemotherapy begins. You can discuss these options with the study doctor.

You should take the study drug/placebo dissolved in a full glass (8 ounces) of water. You may take it with or without food, but if it causes an upset stomach, you should take it with food.

If you have trouble swallowing the dose of study drug/placebo, you can open the capsule right before you take it. You should not lie down for at least 30 minutes after taking the study drug/placebo to reduce the risk of side effects.

You must bring the study drug/placebo container (along with any remaining drug/placebo) to every study visit.

Study Visits:

Before you start your treatment with the study drug/placebo:

* If you can become pregnant, blood (about 2 teaspoons) will be drawn for a pregnancy test. If the pregnancy test is positive, it will be repeated after 48 hours to make sure you are pregnant. Sometimes, cancer can cause a "false positive" on a pregnancy test.
* You will complete 2 questionnaires about pain and other symptoms, and your quality of life. It should take about 5-8 minutes to complete all of the questionnaires.
* If possible, blood (about 2 tablespoons) will be drawn to test for markers of inflammation. Markers of inflammation are found in the blood and may be related to your symptom development.
* Your demographic information, such as your marital status, job status, education, and race will be recorded.

Before you start your chemotherapy treatment:

°If possible, blood (about 2 teaspoons) may be drawn to test for markers of inflammation, only if you started treatment with the study drug/placebo while you waited for your CVC to be placed for chemotherapy. If you choose to wait to start the study drug/placebo until chemotherapy begins, this blood sample will not be drawn.

During treatment with the study drug/placebo:

* You will complete the symptom questionnaire 2 times each week during the first cycle and 1 time each week during any remaining cycles. The symptom questionnaire asks about any symptoms you may be having and how they may be affecting your daily activities. You will also complete the quality of life questionnaire. The questionnaires should take about 3-5 minutes to complete each time.
* You will complete the questionnaires in paper-and-pencil format or on an electronic tablet PC if you are in the clinic. When you are away from the clinic you will complete the questionnaires on the telephone or on your computer.
* If possible, during your clinic visits at the start of cycle 2, 3, and 4 (if applicable), blood (about 2 tablespoons) may be drawn to test for markers of inflammation.

At the end of study drug/placebo treatment:

When you have finished taking the study drug/placebo, the study staff will contact you to complete a questionnaire asking you about your opinions of the study drug/placebo. This questionnaire will take about 3-5 minutes to complete.

Length of Study Participation:

You will be on study for up to 8 weeks, if there is no delay in starting your chemotherapy cycles. You will take the study drug/placebo for up to 8 weeks. You will be taken off study early if the disease gets worse, you have intolerable side effects, if you are unable to follow study directions, or the study doctor thinks it is in your best interest.

End-of-Study Visit:

At the end of the last study cycle after you complete the symptom treatment, you will complete questionnaires about pain and other symptoms and your quality of life. It should take about 3-5 minutes to complete the questionnaires. If possible, blood (about 2 tablespoons) may be drawn to test for markers of inflammation.

Follow-Up:

The study staff will call you 30 days after you finish taking the study drug/placebo to ask about any side effects you may be having. This call should last about 5 minutes.

This is an investigational study. Minocycline is FDA approved and commercially available for the treatment of bacterial infection. Using minocycline to try to reduce the side effects of chemotherapy in patients with pancreatic cancer is investigational.

Up to 76 patients will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Minocycline 100 mg by mouth two times a day (200 mg/day). Initial Dose (starts on first day of run-in phase or chemotherapy). Questionnaires completed at baseline, 1 time each week during drug/placebo administration, and at end of study visit. arm 2: Matching placebo capsules by mouth twice a day. Initial Dose (starts on first day of run-in phase or chemotherapy). Questionnaires completed at baseline, 1 time each week during drug/placebo administration, and at end of study visit.

Interventions: intervention 1: Minocycline intervention 2: Placebo intervention 3: Questionnaires
Intervention descriptions: intervention 1: 100 mg by mouth two times a day (200 mg/day). intervention 2: Matching placebo capsules by mouth twice a day. intervention 3: Questionnaires completed at baseline, 1 time each week during drug/placebo administration, and at end of study visit.

Protocol document:
Prot_SAP_000.pdf: 
2012-0587
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Protocol Page
A Randomized, Placebo Controlled-double Blind Study of Minocycline for 
Reducing the Symptom Burden for Pancreatic Cancer Patients 
2012-0587
Core Protocol Information
Short Title 
Minocycline randomized study in pancreatic cancer patients
Study Chair: 
David Fogelman
Additional Contact:
Angele K. Saleeba
Araceli G. Garcia-Gonzalez
Xin Shelley Wang
Department:
Symptom Research
Phone:
713-745-3470
Unit:
1450
Full Title: 
A Randomized, Placebo Controlled-double Blind Study of Minocycline for Reducing the 
Symptom Burden for Pancreatic Cancer Patients 
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Terminated 09/20/2018
Version:
11
Submitted by:
Angele K. Saleeba--10/3/2017 8:37:26 AM
OPR Action:
Accepted by:  Elizabeth Orozco -- 10/4/2017 1:42:44 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: To establish the efficacy of minocycline in reducing symptoms 
during a cycle (14 days) of FOLFIRINOX* or gemcitabine-based chemotherapy in 
patients with  pancreatic cancer. Our working hypothesis is that patients randomized to 
receive 200mg/day minocycline will report less severe fatigue, pain, disturbed sleep, 
lack of appetite, and drowsiness, compared with a placebo group. 
* References to FOLFIRINOX in this protocol include modified versions of the treatment, 
such as FOLFOX. Treating oncologists may alter the FOLFIRINOX combination 
depending on the patient’s condition. 
1.2
Secondary outcomes: 
1.21: To establish the efficacy of minocycline in reducing symptoms beyond the first 
cycle of FOLFIRINOX or gemcitabine-based chemotherapy in patients with pancreatic 
cancer. Our working hypothesis is that patients who receive up to 4 cycles of 
chemotherapy and who are randomized to receive 200 mg/day minocycline will report 
less severe fatigue, pain, disturbed sleep, lack of appetite, and drowsiness compared 
with a placebo group. 
1.22: To characterize the effect of minocycline on modulating inflammatory biomarkers 
and their possible association with dynamic changes in symptom burden in patients 
diagnosed with pancreatic cancer. Our working hypothesis is that patients undergoing 
chemotherapy who receive minocycline will exhibit reduction in concentrations of 
circulating inflammatory markers, compared with a placebo group. 
1.23: To examine the potential effects of minocycline on preventing rapid increase of 
cytokine release in patients with mild baseline symptoms. Our working hypothesis is that 
patients receiving minocycline will exhibit a slower rate of increase in biomarkers (IL-6 
and sTNF-R1), compared with a placebo group.
1.24: To examine the effect of minocycline on muscle and fat mass and wasting:  We 
will compare CT images pre and post treatment to measure changes in fat and muscle 
mass.  We will then compare these measurements with baseline symptoms and 
cytokines and changes in these measures.
1.25: To examine the effect of minocycline on managing disease-driven symptoms for 
about 2 weeks before the start of chemotherapy. Our working hypothesis is that patients 
who have 2 weeks (+/- 2 weeks) as a  run-in phase intervention with minocycline will 
benefit from reduced baseline symptom severity and reduced inflammatory activity 
before chemotherapy.
1.26: To characterize the effect of FOLFIRINOX and disease progression on the 
development of high symptom burden in patients diagnosed with pancreatic cancer. 


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2.0 Rationale
Nearly 75% of patients with pancreatic cancer experience a rapid and merciless course of 
intractable pain, fatigue, poor appetite, distress, and death within the first 12 months of 
diagnosis. Over the past 30 years, extensive clinical research has focused on reversing 
cachexia and wasting by using growth factors, anabolic steroids, and food supplements. Other 
researchers have worked to identify prognostic factors from inflammation biomarkers and tumor 
markers. However, this paradigm has not been a great help for reducing the high symptom 
burden produced by this very lethal cancer, especially when the disease is not resectable (Yip 
et al., 2006).
The recent randomized phase III trial reported by Conroy et al (NEJM, 2011) is a major 
therapeutic advance in the management of patients with a confirmed metastatic pancreatic 
cancer. A combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, 
and leucovorin (FOLFIRINOX) improved overall survival as compared with gemcitabine as 
first-line therapy in selected patients with metastatic pancreatic cancer. This study indirectly 
suggests new insights for patients with unresectable locally advanced, but nonmetastatic, 
pancreatic carcinoma (LAPC). Recent studies examined this regimen used as neoadjuvant 
therapy for newly diagnosed unresectable locally advanced pancreatic cancer patients (Levy A, 
et al, 2012; Hosein et al., 2012). In the era of new effective cytotoxic agents (platinum 
compounds, taxanes, and other third-generation chemotherapies), targeting the subclinical 
disease or the early metastatic step of pancreatic cancer could be the cornerstone of new 
advances in curative-intended strategy. In the Conroy et al study, quality of life at 6 months was 
significantly higher in the FOLFIRINOX arm, with twice fewer patients having a definitive 
degradation of their quality of life than that in the gemcitabine group (31% vs 66%; hazard ratio, 
0.47; 95% confidence interval, 0.30–0.70; P < 0.001). However, acute toxicity was increased 
significantly in the experimental arm versus the gemcitabine arm of this Phase III trial, with 
symptoms ranging from fatigue, vomiting, and diarrhea to sensory neuropathy. In some cases, 
treating oncologists modify the FOLFIRINOX regimen for sicker patients in order to reduce 
toxicity and improve tolerability, and studies have shown that such modifications do not 
adversely impact the efficacy of the treatment (Gunturu et al, 2013; Mahaseth et al, 2013). 
Nonetheless, FOLFIRINOX is an aggressive therapy, and a strategy to reduce symptom burden 
during the acute treatment phase may help patients remain in treatment for their cancer.  
Typically diagnosed with advanced disease, patients with pancreatic cancer suffer from high 
symptom burden during their limited survival period. Their most disturbing symptoms—often 
fatigue, poor appetite, drowsiness, disturbed sleep, pain, and distress—present a serious 
challenge for patient care. The underlying mechanisms and signaling pathways involved in 
human symptom experiences are not yet well understood. The role of peripheral inflammation 
in producing a number of centrally mediated physiological and behavioral changes has been 
widely studied across many chronic diseases; however, for cancer specifically, the effect of 
peripheral and central inflammation as a common mechanism underlying the development of 
multiple symptoms due to disease/therapy has only been hypothesized. Lack of confirmative 
evidence of such association becomes a key problem for providing effective, mechanism-driven 
symptom control for patients with cancer. 
Based on animal studies of sickness behavior (Dantzer, 2001), we theorize that many of the 
symptoms of cancer and its treatment are related to cytokine dysregulation (Cleeland et al., 
2003; Lee et al., 2004). The fluctuations in inflammatory cytokines, primarily interleukin (IL)-1, 
IL-6, and tumor necrosis factor (TNF)-a, are related to fluctuations in components of sickness in 


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animals (anorexia, disturbed sleep, hyperalgesia, disrupted learning). It is well recognized that 
p38 mitogen-activated protein kinase (MAPK) enhances the access of inflammatory cytokines 
to the brain via leaky regions in the blood-brain barrier. Active transport molecules and afferent 
nerve fibers may also activate sickness behavior (Maier et al., 1998; Raison et al., 2006). 
Microglia-dependent TNF-a–mediated increase in CNS excitability provides further insight into 
potential mechanisms underlying disparate neurological and behavioral changes associated 
with chronic inflammation.
Although inflammatory mechanisms have been investigated with clinical outcomes in pancreatic 
cancer, to our knowledge, no study has examined whether downregulating a network of 
cytokines would be helpful for symptom reduction, especially for the most severe symptom, 
fatigue; this is our primary objective for this proposed study. On the basis of strong evidence 
that minocycline has a wide range of anti-inflammatory effects in the brain and peripheral 
system, which it accomplishes by inhibiting microglial activation and proliferation through 
inhibition of the p38 MAPK pathway, we propose a Phase II, 2-arm, double-blind, 
placebo-controlled randomized study in patients with newly diagnosed pancreatic cancer. 
Our proposed study is innovative because minocycline, although used widely as an 
anti-inflammatory agent in other chronic conditions, has never been tested for improving 
symptoms in pancreatic cancer to confirm the central hypothesis of inflammation as a 
mechanism for cancer-related symptom development. Minocycline’s capacity to cross the 
blood-brain barrier makes it desirable for testing the role of inflammatory cytokines in producing 
symptom burden. The positive results may immediately help patients with pancreatic cancer live 
with fewer symptoms during limited survival and will support a mechanism-driven approach to 
managing cancer-related symptoms with this low-toxicity drug. Finally, positive results in 
humans would set the stage for a future R01 proposal with phase III trial in this cohort of 
patients to confirm that the manipulation of peripheral and central inflammation by 
anti-inflammatory agents such as minocycline will relieve multiple symptoms. 
3.0 Background
3.1 Pancreatic Cancer, High Symptom Burden, and Inflammation 
Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States, 
where an estimated 42,500 Americans were diagnosed with pancreatic cancer in 2009 and 
more than 35,000 were expected to die from the disease (Jemal et al., 2009). Survival for 
regional pancreatic cancer has improved in the past decade, most strikingly for patients 
undergoing neoadjuvant chemotherapy and resection (Riall et al., 2006), while overall survival 
has increased only a few months for patients with metastatic disease, at the cost of significant 
toxicity (Moore et al., 2007; Conroy 2011). 


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Patients living with unresectable pancreatic cancer suffer from multiple severe symptoms, 
including pain, fatigue, cachexia, depression, bowel dysfunction, and infection. The “symptom 
burden” produced by these multiple symptoms reduces functioning and quality of life (Kelsen et 
al., 1997). The most disturbing symptoms of patients with advanced pancreatic 
cancer—fatigue, loss of appetite, and impaired sense of well-being—were reported in a recent 
prospective study (Labori et al., 2006). Nonetheless, MacDonald (2007) subsequently pointed 
out that “lack of emphasis on symptom studies is disproportionate to their importance to 
patients and their families” for advanced cancer. Despite the assistance of nutrition and pain 
management consultants (Wong et al., 2004), the methods for effective symptom control are 
limited, especially for some of the most distressing symptoms that this disease produces, such 
as those related to fatigue. 
3.2 Inflammatory Cytokines, Sickness Behavior, and Cancer-Related Symptoms
Multiple cancer symptoms closely parallel the sickness behaviors observed in animals after 
administration of inflammatory agents (Dantzer, 2009; Hart, 1988; Kent et al., 1992; Lee et al., 
2004; Miller et al., 2008). Laboratory studies have identified certain inflammatory cytokines 
(tumor necrosis factor [TNF]-a, interferon (IFN)-g, interleukin [IL]-1, and IL-6) as central 
mediators of sickness behavior resulting from infections (Kelley et al., 2003). Somewhat 
independently, researchers have proposed inflammation as a candidate mechanism for 
expression of cancer-related symptoms, and modulation of this inflammation as representing a 
potential pathway for the clinical prevention and treatment of these symptoms (Miller, 2003; 
Wang et al., 2010a; Wood et al., 2006). 
In both advanced and inoperable pancreatic cancer there is evidence for the role of the 
inflammatory response in the development of cachexia and in determining prognosis (McKay et 
al., 2008; Seruga et al., 2008). A high level of IL-6 is an independent predictor of shorter overall 
survival in patients with pancreatic cancer (Ebrahimi et al., 2004). Serum IL-6 is correlated with 
staging and size of pancreatic cancer (Chen & Huang, 2009; Talar-Wojnarowska et al., 2009). 
As long as a decade ago, researchers reported that a set of inflammatory cytokines, rather than 
a single cytokine, work in concert in cachexia (Matthys & Billiau, 1997).  
3.3 Basic and Clinical Studies for Palliative and Supportive Care in Pancreatic Cancer
Research suggests that even when cancer has not metastasized extensively, metabolic 
changes, including alterations in resting energy expenditure, are occurring. Although the 
mechanisms remain unknown, corticosteroids and megestrol acetate are widely used for 
palliating anorexia. Murine and human research has evidenced a stereotypical set of 
pathological changes that occur as pancreatic cancer develops, and whereas weight loss 
generally tracks disease progression, there is a significant lag between behaviors indicative of 
pancreatic cancer pain and disease progression (Lindsay et al., 2005). This evidence suggests 
that early mechanism-driven symptom prevention might reduce symptom burden in pancreatic 
cancer. 
3.4 Assessing the Symptoms of Pancreatic Cancer


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Symptoms and health-related quality-of-life assessments are gradually being integrated into 
oncology clinical research and practice, including pain management. For more than a decade, 
systematic assessment via patient-reported outcomes (PROs) has been used to evaluate the 
clinical impact of new therapies for pancreatic cancer. The US Food and Drug Administration 
has promoted the use of PRO measures in clinical trials (US Food and Drug Administration et 
al., 2009), and there is a dawning recognition that asking patients directly about their 
cancer-related symptom burden using the same scientific rigor required of other clinical 
outcomes can provide valuable data for prognosis, treatment, symptom management, and 
supportive care (Cleeland, 2007; Müller-Nordhorn et al., 2006). Clinical studies have challenged 
the assumption that response rate and survival are the only appropriate endpoints for clinical 
trials in measures of treatment efficacy. 
3.5  Symptom Management
The control or prevention of cancer-related cytokine dysregulation presents new opportunities 
for symptom reduction or prevention. Just as with optimal curative cancer treatments, optimal 
symptom management is highly likely to be dependent on combinations of treatments with 
different targets of action (mechanistic, empiric, behavioral) (Miller, 2003). Thus, a goal of the 
proposed study is the development of symptom-management strategies based on underlying 
symptom mechanisms in combination with empiric treatments. Inflammation can be modulated 
by a variety of existing pharmaceutical approaches. 
Better symptom management, in cancer as well as in other diseases, has been hampered by 
the lack of a strong clinical-trial evidence base for guiding symptom management practice. 
Several barriers have hindered the development of clinical trials in symptom management. The 
subjective nature of symptoms has limited innovative research into the mechanisms underlying 
these symptoms and the development of novel ways of treating or preventing them. However, 
patient-reported outcomes research has recently been promoted by the U.S. Food and Drug 
Administration (FDA) for more accurate evaluation of therapeutic agents, and symptom 
reduction has been recognized as a primary clinical benefit for drug approval (US Food and 
Drug Administration et al., 2009).
Other barriers have hindered development of evidence-based methods for controlling 
treatment-related symptom burden, despite the availability of adequate symptom-measurement 
methods. Many of the agents that might be effective in the control of treatment-related 
symptom burden are generic or off-patent drugs that will never receive clinical research support 
from the pharmaceutical industry because there is no financial incentive to support clinical trials 
testing their effectiveness for symptom control. Additionally, the control of treatment-related 
symptoms almost always involves the use of combined treatment modalities, which are difficult 
to evaluate using traditional clinical trial methods. 
Current practice utilizes randomized clinical trials to manage a single symptom with a single 
agent, for example, pain controlled with a single analgesic. When clinicians do treat multiple 
symptoms, they have few options in agents to prescribe on the basis of evidence-based 
research that would address multiple symptoms. The proposed study aims to investigate the 
effects of treatment on multiple symptoms and on inflammation mechanisms using one agent, 
minocycline. 


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This study is a minocycline intervention during 3-4 cycles of FOLFIRINOX or 
gemcitabine-based chemotherapy. The primary outcome will be the first cycle (2 weeks) of 
intervention. The short, 2-week intervention period is based on research in which symptom 
reduction was the primary outcome of intervention trials in patients with advanced cancer 
(Bruera et al, 2013; Yennurajalinggam et al, 2013). This strategy is designed to investigate the 
effectiveness of a trial agent on symptom reduction due to both disease and chemotherapy 
while avoiding the confounding issues of patient drop-off and increase in symptom burden 
induced by disease progression. The secondary outcomes of the trial will include continued 
study during the intervention for 3-4 cycles chemotherapy. Continued observation of the effect 
of minocycline in responders who are in good compliance with their chemotherapy will provide 
further evidence of symptom reduction related to accumulated anti-inflammatory effect.
4.0 Background Drug Information
Minocycline hydrochloride (Minocin®, manufactured by Triax Pharmaceuticals, LLC, Cranford, 
NJ) is an inexpensive, widely used, semisynthetic antibiotic derived from tetracycline that has 
strong preclinical and clinical evidence of anti-inflammatory effects. Minocycline has the unusual 
side effect of markedly suppressing proinflammatory cytokine release, the primary reason we 
will include it as an intervention in this study. See Appendix D. 
4.1 Minocycline: Inhibiting Activation and Proliferation of Microglia
Minocycline is a synthetic antibiotic tetracycline that has been shown to possess 
anti-inflammatory, antiviral, and antioxidant properties (Mishra & Basu, 2008). It is a lipophilic 
molecule readily absorbed across the blood-brain barrier (Aronson, 1980). In pure microglia 
cultures, glutamate-induced transient activation of p38 mitogen-activated protein kinase 
(MAPK) was inhibited by minocycline (Tikka et al., 2001). Inhibition of p38 MAPK is considered 
to be the mechanism underlying minocycline’s anti-inflammatory, non-antibiotic effects (Sapadin 
& Fleischmajer, 2006). Minocycline has the unusual side effect of markedly suppressing 
proinflammatory cytokine release, the primary reason we will include it as an intervention in this 
study to effect broad cytokine blockade.  
Preclinical data suggest that minocycline reduces neural inflammation and prevents apoptosis 
of neural cells. Animal studies have shown that minocycline reduces the levels of the 
proinflammatory cytokines IL-6, TNF-a, IL-1β and IFN-γ (Ledeboer et al., 2005). This effect, 
along with the inhibition of microglial activation caused by nerve damage, has been shown to 
have neuroprotective action in animal models of a number of diseases, including stroke, 
diabetic retinopathy, multiple sclerosis, and Parkinson’s disease. Minocycline’s 
anti-inflammatory effect prevents subacute pathological change in lungs due to inflammation 
produced by peripheral lipopolysaccharide administration (Yamaki et al., 1998). It effectively 
modulated mechanical hyperalgesia in newly developed animal models and prevented loss of 
intraepidermal nerve-fiber density in oxaliplatin-treated rats (Boyette-Davis & Dougherty, 2011). 
In a rat model of neuropathy, minocycline affected the development of hypersensitivity 
(Raghavendra et al., 2003).
Common side effects of minocycline include light-headedness, vestibular symptoms, headache, 
and nausea (Gump et al., 1977), without correlation between serum concentration and toxicity. 
Another side effect is photosensitization. 


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4.2 Minocycline: clinical studies
Recent clinical trials for Fragile X Syndrome (Paribello et al., 2010), vitiligo (Parsad & Kanwar, 
2010), and schizophrenia, in which minocycline was used to block nitric oxide-induced 
neurotoxicity (Levkovitz et al., 2010), have shown a significant benefit from this well-tolerated 
agent. Minocycline was found to decrease levels of IL-6 and the acute-phase response protein 
CRP in patients with rheumatoid arthritis (Kloppenburg et al., 1996), and it is now widely used to 
managed dermatitis associated with targeted therapy in cancer. Minocycline was safe and 
effective for patients with rheumatoid arthritis in a 48-week double-blind placebo-controlled trial, 
with no serious toxicities and similar side effects in both groups (Tilley et al., 1995). Its 
long-lasting effects for preventing neuropathic pain (Padi & Kulkarni, 2008; Raghavendra et al., 
2003) and as a potential 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.
4.3
Absolute Contraindications to Study Symptom Intervention Agent Minocycline
4.31
Hypersensitivity to any tetracyclines
4.32
Pregnancy
4.33 
Hepatotoxicity (=aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT); 2 times the upper limit of normal)
4.4 
Minocycline Common Adverse Reactions
4.41 
Minocycline: dizziness (9%) and vertigo
4.5 
Minocycline Monitoring Parameters
4.51 
Minocycline: LFTs, BUN, Sr Cr
4.52 
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.


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4.6 
Minocycline Drug Interactions 
4.61
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
4.62
Methoxyflurane anesthesia, when concurrent with minocycline, may cause fatal 
nephrotoxicity
4.63
Retinoic acid derivatives: may increase risk of pseudotumor cerebri
4.64
Warfarin: hypoprothrombinemic response may be increased with tetracyclines; 
monitor INR closely during initiation or discontinuation
4.65
Storage information: at 20°C to 25°C (68°F to 77°F)
References for intervention agents:
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 
4.    Lexi-Comp: Minocycline. http://www.lexi.com/
5.
Clinical Pharmacology: Minocycline 
4.7 
Serious Adverse Events for Symptom Drugs
References: 
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. http://www.drugs.com/pro/minocycline.html
5.0 Study design
5.1 Randomized Controlled Trial of Minocycline vs. Placebo


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We will conduct a two-arm, placebo-controlled randomized study, with a run-in phase, to 
obtain preliminary estimates of the treatment effects of minocycline in patients (N=76) 
diagnosed with pancreatic cancer, who are beginning or have begun chemotherapy. We will 
also assess the safety of minocycline, and the results from this pilot study will inform 
subsequent symptom-management clinical trials. Overall Objective: To develop 
evidence-based strategies for preventing or ameliorating symptoms produced by aggressive 
cancer and chemotherapy.
Study Period:
1. Run-in pilot phase: 2 weeks (+/- 2 weeks) prior to initiation of chemotherapy (e.g. during 
patients waiting time for biopsy or placement of central lines for chemotherapy). This run-in 
phase is not mandatory.
2. Minocycline intervention during a minimum of 1 and maximum of 4 cycles of FOLFIRINOX or 
gemcitabine-based chemotherapy (up to 8 weeks). The primary outcome will be assessed from 
the first cycle (2 weeks) of intervention. The secondary outcomes of the trial will include 
continued study during the intervention for a minimum of 1 and maximum of 4 cycles 
chemotherapy (up to 8 weeks).
Primary Outcome Variable: Average area under the curve (AUC) using the average of  five 
targeted symptoms (fatigue, pain, disturbed sleep, lack of appetite, and drowsiness) and 
divided by the number of weeks of therapy received. This measurement  does not include the 
run-in phase. 
The AUC is calculated using a trapezoidal approximation.  The area of a trapezoid is derived by 
multiplying half of the base with the sum of the 2 heights. The base is the number of days in 
between 2 administrations of the M. D. Anderson Symptom Inventory (MDASI). The 2 heights 
correspond to the 2 mean symptom scores computed at each of these assessments. The AUC 
is measured in units of mean MDASI score in days. The area for the subsequent trapezoid can 
be calculated in the same way. Given a weekly assessment schedule, there will be 
approximately 5 trapezoids during the first cycle (baseline plus twice-a-week data for 2 weeks). 
The AUC is the sum of the area of the 5 trapezoids. The averaged AUC will be the total AUC 
divided by the number of data time points.
Baseline assessments are to occur prior to start of study drug. Administration of the symptom 
intervention agent will commence within 2 days of the start of the next chemotherapy cycle after 
study enrollment.
The pilot study will be placebo controlled and double blinded. This is especially important in 
trials where symptom reduction is the outcome and where knowledge of the treatment arm 
might bias assessment staff.
All grade 3 and 4 toxicities observed during the trial will be evaluated by the principal 
investigator (PI) in consultation with the treating physician, or by another attending physician if 
the PI is not available, to determine if the toxicities were caused by minocycline (rather than the 
primary chemotherapy agent) and to decide whether to remove the patient from the trial (see 
10.1 for unblinding procedure). 


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The table below displays the symptom intervention agent and the dosing schedule (Lexi-Comp). 
Symptom 
Intervention Agent
Dosage Forms
Initial Dose (starts 
on first day of 
run-in phase or 
chemotherapy)
Initial Dose (starts on 
first day of run-in phase 
or chemotherapy)
Minocycline
100 mg 
capsules
100 mg two times a 
day (200 mg/day)
Matching placebo
Minocycline is commercially available as 50 mg, 75 mg, and 100 mg capsule or tablet. It can be 
taken with or without food and should be stored (packaged) protected from light.
5.2 
Observational Arm
Because symptom profile information on patients with pancreatic cancer treated with 
FOLFIRINOX is lacking, an observational study of these patients will provide valuable 
information to patients and clinicians about the high symptom burden associated with the 
interaction between  this aggressive therapy and rapid disease progression. We will enroll 
patients who receive FOLFIRINOX chemotherapy but who either do not qualify for the 
minocycline intervention study or elect not to participate in it. Overall objective: To 
characterize the effect of FOLFIRINOX and disease progression on the development of 
symptom burden in patients diagnosed with pancreatic cancer. 
Study Period:  
1. Run-in pilot phase: 2 weeks (+/- 2 weeks) prior to initiation of chemotherapy (e.g. while 
patient is waiting for biopsy or placement of central lines for chemotherapy). This run-in phase 
is not mandatory.
2. Symptom assessment during a minimum of 1 and a maximum of 4 cycles of FOLFIRINOX 
chemotherapy (up to 8 weeks). 
Primary Outcome Variable: 
Severity of MDASI symptoms at baseline and follow-up assessments. 
6.0 Patient Eligibility
6.1
Inclusion Criteria 
6.11 
Minocycline Trial only: Patients with a pathological or clinical diagnosis of 
pancreatic cancer and beginning or continuing FOLFIRINOX or 
gemcitabine-based chemotherapy.
6.12     Observational Arm only: Patients with a pathological or clinical diagnosis of 
pancreatic cancer and beginning or continuing FOLFIRINOX chemotherapy.


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6.13 
Patients > 18 years old.
6.14
Minocycline Trial only: Patients with ECOG PS = 0-2.
6.15
Patients who speak English or Spanish (due to MDASI language options, we are 
only accruing English-speaking or Spanish-speaking patients to the protocol).
6.16
Patients willing and able to review, understand, and provide written consent 
before starting therapy.
6.17
Minocycline Trial only: Patients with adequate renal function according to MD 
Anderson testing standards (screening cut off for serum creatinine < 2 times the  
upper limit of normal).
6.18
Minocycline Trial only: Patients with adequate hepatic function according to MD 
Anderson testing standards (screening results for total bilirubin must be  < 2 
times the upper limit of normal; screening results for alanine aminotransferase 
(ALT) must be < 3 times the upper limit of normal; screening results for aspartate 
aminotransferase (AST), if available, must be < 3 times the upper limit of 
normal).
6.2
Exclusion Criteria 
6.21
Minocycline Trial only: Patients who are taking medication or have conditions 
that potentially preclude use of minocycline, as determined by the treating 
physician.
6.22
Patients who are enrolled in other symptom management clinical trials.
6.23 
Minocycline Trial only: Patients who currently have bile duct obstruction or 
cholelithiasis.
6.24
Minocycline Trial only: Patients with hypersensitivity to any tetracyclines.
6.25
Minocycline Trial only: Patients who are pregnant. Pregnancy will be confirmed 
by negative urine test; patients with a positive urine test will be retested for 
doubling of HCG 48 hours after the first test, because of beta-HCG’s role as a 
tumor marker. Patients without such a rise will be eligible for the study and will 
be enrolled at the investigator’s discretion.
6.26
Minocycline Trial only: Patients who are under treatment of warfarin with INR > 
1.5.
6.27
Patients who, in the judgment of the investigator, may be unable to participate in 
the required study procedures.


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6.28  Minocycline Trial only: Patients who have had prior treatment for pancreatic 
cancer within the past six months may be excluded at the discretion of the 
investigator.
7.0 Study Procedures
7.1 
Patient Enrollment and Registration
Patients will be screened for eligibility and recruited for enrollment in the outpatient GI 
Medical Oncology Clinic. The opportunity to participate in the minocycline trial will be 
presented to eligible patients. Those who opt not to enroll in the minocycline study, 
along with those who do not qualify for the minocycline study, will be approached about 
participating in the observational arm. Research staff will maintain a log of all patients 
screened, and the reasons that patients do not enter the study will be documented. 
Eligible patients who agree to enroll in the study will provide written informed consent. 
Enrolled patients will be registered into the institutional patient data management 
system. 
7.2
Randomized Controlled Trial of Minocycline vs. Placebo
7.21 
Patient Randomization and Assignment to Treatment Arm
The minocycline study will accrue a total of 76 patients, with 38 patients each in 
the intervention and placebo arms. Prior to accruing the first patient, a 
randomization list for the entire sample will be generated by our biostatistician 
collaborator from the Department of Biostatistics, stating into which group a 
patient will be randomized. This list containing the accrual number and treatment 
group information will be set up in the Clinical Trial Conduct website.
Once a patient is enrolled on the study, the Investigational Pharmacy retrieves 
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. The patient 
visits the most convenient outpatient pharmacy to pick up the study medication 
assigned.
Patients will pick up the assigned study medications at one of the outpatient 
pharmacy stations in MD Anderson, or study medication will be mailed to the 
patient by the MD Anderson pharmacy. Patients will be given instruction in how 
to take study medications. The participants will take study medication enterally, 
twice daily, after study entry. The final day of study medication is the final day of 
the chemotherapy cycle after a maximum of 4 cycles after medication is started 
or at the time of discontinuation of FOLFIRINOX or gemcitabine-based 
chemotherapy, whichever is earlier; this does not count the optional run-in 
period. Total daily doses will be dispensed. Study medication use will be 
reviewed by study staff. 
Study staff will contact patients every two weeks to check for adverse events 


2012-0587
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during routinely scheduled clinic visits or via telephone calls. 
At enrollment, patients will be informed that they will receive a stipend in the 
maximum 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 at the first 3 cycle start dates after they are enrolled in 
the study and if they remain on study.
7.22 
Potential Confounding Impact from Palliative Care
Because of the high level of symptom burden typically experienced by this cohort 
of patients, both new and widely adapted supportive care other than the agent to 
be tested may emerge over the time of the study and might affect symptom 
burden. Agents that could modify inflammation, such as the nutritional 
supplements curcumin and fish oil, and megestrol (an FDA-approved agent) for 
managing cachexia, will be allowed for both groups of patients. We expect that 
changes in symptom severity that can be attributed to changes in primary 
treatment regimen or other covariates can be incorporated into study at any point 
during the trial's conduct, and that documented data can be incorporated into this 
regression equation in a straightforward manner.
7.3
Observational Arm
A total of 45 patients will be accrued for the observational arm. Patients will be under the 
same assessment schedule as patients in the minocycline trial.  
8.0 Data Collection
With a few exceptions as noted below, data collection will be the same for both the minocycline 
trial and the observational study. Multiple symptoms will be monitored weekly using the 
gastrointestinal cancer module of the MDASI (MDASI-GI; Wang et al., 2010b) to simultaneously 
document symptom prevalence, severity, and interference. We will concurrently track markers 
of inflammation to establish correlations with symptom development.
Research staff will collect other data for all patients: demographics, co-morbidities, cancer 
therapy and tumor response, ECOG PS, weight changes, infections, routine lab results, 
symptom-control and palliative care.
8.1 
Patient-Reported Outcome (PRO) Measurements
8.11 
Symptom Measurement (Appendix G)
Symptom data will be collected using the MDASI GI module prior to the start of 
the first chemotherapy cycle after the patient is enrolled in the study, twice a 
week during the first chemotherapy cycle, and weekly during the 2-week run-in 
phase and subsequent chemotherapy cycles for a maximum of 12 weeks. 


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8.12 
Measure of Global Quality-of-Life Rating (QoL) (Appendix H) 
The reporting of symptom severity has been shown to be correlated with other 
self-report measures, especially quality-of-life ratings, including a single-item 
global quality of life (GQL) rating (Mendoza et al., 2002). This single-item rating 
of current quality of life is measured on a 0-10 scale, bounded by worst ever and 
best ever (Sloan et al., 1998). The GQL will be administered prior to the start of 
the first chemotherapy cycle after the patient is enrolled on the study and weekly 
thereafter. It will be used as a time-varying covariate in assessing changes in 
symptoms and longitudinally for secondary exploratory analyses of the effects of 
interventions on patients’ overall impression of quality of life. 
8.13
Measure of Patient Satisfaction with Study Medication Satisfaction Scale 
(Appendix I) - Minocycline Trial Only
The Study Medication Satisfaction Scale is a short, 7-item scale that asks 
patients about several areas of satisfaction. The scale includes questions about 
ease or difficulty of taking the medication in general and in its current form, 
convenience of taking the study medications as instructed, and patient 
confidence that the study medication is of benefit. 
8.14
Remote PRO Data Capture 
PRO questionnaires can be administered in several formats, including 
paper-and-pencil (both in the clinic and by mail), face-to-face or telephone 
interview, and secure, institutionally approved electronic means (such as tablet 
PC or REDCap).
Study data may be collected and managed using REDCap (Research Electronic 
Data Capture) electronic data capture tools hosted at MD Anderson (Harris et al, 
2009. REDCap (www.project-redcap.org) is a secure, web-based application with 
controlled access designed to support data capture for research studies, 
providing: 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 
Cancer Center'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 was 
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 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 


2012-0587
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number. Following publication, study data will be archived in REDCap.
8.2 
Other Data to be Collected 
Research staff will collect demographic and clinical information from the patient's 
medical record. Demographic data to be collected may include such items as birth date, 
marital status, race/ethnicity, education, and employment status. Examples of clinical 
information that may be collected at one or more timepoints during the study include 
height and weight, disease information (eg, cancer diagnosis/stage), treatment 
information (eg, chemotherapy agents, current medications), comorbidities, and 
performance status. 
Laboratory values from blood analysis, such as C-reactive protein (CRP),  serum 
chemistry (albumin, calcium, phosphorous, glucose, BUN, creatinine, total bilirubin, and 
total protein), electrolytes (sodium, potassium, chloride, carbon dioxide, magnesium), 
and complete blood count (CBC), will be recorded if they are available in the patient 
medical record from a blood draw performed for clinical purposes.
8.3 
Cytokine Data Collection 
We will concurrently track the serum concentrations of a panel of inflammatory markers  
(e.g. IL-1RA, IL-6, IL 8, IL-10, sTNF-R1, MCP-1, midkine, CRP, CXCL16). 
In addition to routine blood testing, up to 5 blood samples (if the patient will have a 
run-in phase) or up to 4 blood samples (if the patient will start the chemotherapy 
immediately) will be assayed for inflammatory markers: (1) at baseline, upon enrollment 
into the study (before intervention treatment begins); (2) at the start of the 2nd, 3rd, and 
4th chemotherapy cycles, if applicable; and (3) at the end of the last chemotherapy 
cycle (end of study). The end-of-intervention sample, if available, will provide information 
about any differences in treatment effects between the two arms.
During the patient’s routine clinic visits, 10 mL of blood will be drawn in a red stopper. 
The tube will be placed at 4°C within 15 minutes of phlebotomy and transferred to the 
research laboratory within  a maximum period of 2 hours. The sample will be processed 
immediately once received by the research lab. Briefly, dispensed in 0.5 mL 
cryopreservation tubes labeled with the subject’s study number and date of collection,  
samples will be stored at -80°C until the cytokine assays. Blood samples will be 
delivered to MD Anderson's Laboratory of Neuroimmunology of Cancer-Related 
Symptoms (NICRS) for processing and cytokine assay. Cytokine levels will be 
measured using Multiplex and ELISA methods. 
8.4 
Assessment Schedules 
8.41
Randomized Controlled Trial of Minocycline vs. Placebo
Run-in or 
chemotherapy + 
minocycline 
start*
Study 
Cycle 1*
Study 
Cycle 2 (if 
applicable)
**
Study 
Cycle 3
(if 
applicable)**
Study 
Cycle 4 (if 
applicable)**
End of 
study (last 
day of last 
cycle)
MDASI-GI
1
X
X
X
X
X
X


2012-0587
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Page 17
QoL
1
X
X
X
X
X
X
Study Medication 
Satisfaction Scale
2
X
X
Patient-Reported 
information 
checklist
X
X
X
X
X
X
Demographic 
Information
X
Disease history, 
current disease 
status
X
CTC Toxicity 
information
X
X
X
X
Other clinical 
information
X
X
X
X
X
Laboratory 
Information
X
X
X
X
X
X
Research Blood 
Sample Collection***
X
X
X
X
X
Medication 
information
X
X
X
X
Study Medication 
Accountability
X
X
X
X
X
Final Status 
information
X
1.
Collected weekly (twice a week during the first cycle), either in the clinic or by phone call or other institutionally approved 
electronic means. Run-in or chemotherapy + minocycline start assessments to occur no more than 12 days before start of 
study cycle 1 of chemotherapy. If patient will participate in the run-in phase, the intervention will be administrated for 2 weeks 
before chemotherapy begins. 
2.
If the patient withdraws before completing the trial, staff will make an effort to collect this form as soon as possible. 
* 
Baseline and Cycle 1 may coincide if no run-in period is completed. In this case, forms are completed only once.
** 
Some patients will receive less than 4 cycles of chemotherapy while on the study. These procedures will be performed only at 
the end of intervention (i.e. at the end of study cycle 2, 3 or 4 depending on the total number of cycles completed while on 
study). 
***
Blood for biomarkers will be collected if possible and if the patient is having routine blood draws at MD Anderson main 
campus. 
8.42
Observational Arm
Baseline 
Study 
Cycle 1
Study 
Cycle 2*
Study 
Cycle 3*
Cycle 4 (if 
applicable)*
End of study 
(end of last 
cycle)
MDASI-GI
1
X
X
X
X
X
X
QoL
1
X
X
X
X
X
X
Patient-Reported 
information checklist
X
X
X
X
X
X
Demographic 
information
X
Disease history, 
current disease 
status
X
Other clinical 
information
X
X
X
X
X
Laboratory Data  
information
X
X
X
X
X
X
Research Blood 


2012-0587
December 18, 2014
Page 18
Sample Collection**
X
X
X
X
X
Final Status 
information
X
  1.
Collected weekly (twice a week during the first cycle), either in the clinic or by phone call or other institutionally 
approved electronic means. Run-in or chemotherapy + minocycline assessments to occur no more than 12 days 
before start of study cycle 1 of chemotherapy. 
* 
Some patients will receive less than 4 cycles of chemotherapy while on study. These procedures will be performed only 
at the end of intervention (i.e. at the end of study cycle 2, 3 or 4 depending on the total number of cycles completed while 
on study). 
**
Blood for biomarkers will be collected if possible and if the patient is having routine blood draws at MD Anderson 
main campus. 
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.
Information gathered for this study will not be reused or disclosed to any other person or entity, 
or for other research. Once the research has been completed, identifiers will be retained for as 
long as is required by law and by institutional regulations, and at that point will be destroyed.
9.0 Adverse Events Reporting
9.1 
Adverse Events (AE) - Minocycline Trial Only
All patients will be contacted weekly by research staff either in person or by telephone to 
closely monitor potential adverse events during treatment. In addition, patients will be 
given a contact phone number for treatment-related questions.
Toxicity and other clinical variables will be collected by research staff at baseline, every 
cycle and end of treatment. 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. (See Appendix C). The PI 
or physician designee is responsible for verifying and providing source documentation 
for all adverse events and assigning the attribution for each event for all subjects 
enrolled on the trial. 
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) 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.


2012-0587
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9.2 
Serious Adverse Events (SAE) - Minocycline Trial Only
A serious adverse event is any adverse drug experience occurring at any dose that 
results in any of the following outcomes: 
Grade 3 or above AE per CTC
z
Death
z
A life-threatening adverse drug experience – any adverse experience that places the 
z
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.
Inpatient hospitalization or prolongation of existing hospitalization
z
A persistent or significant disability/incapacity – a substantial disruption of a person’s 
z
ability to conduct normal life functions
A congenital anomaly/birth defect
z
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 or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32).
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “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 University of Texas MD 
Anderson Cancer Center Institutional Review Board system (UTMDACC IRB), 
regardless of attribution (within 5 working days of knowledge of the event). 
Serious adverse events will be captured from the time the patient signs consent until 30 
days after the last dose of drug. Serious adverse events must be followed until clinical 
recovery is complete and laboratory test values have returned to baseline, progression 
of the event has stabilized, or there has been acceptable resolution of the event.
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy.


2012-0587
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10.0 Criteria for Removal from the Study
10.1 
Unblinding Procedure - Minocycline Trial Only
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, a request for 
unblinding the symptom trial agents for the affected study subject will be sent via email 
to invdrugs@mdanderson.org or phoned into the Investigational Pharmacy Services at 
713-792-2848. The 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 
UTMDACC IRB when unblinding occurs. 
10.2 
Criteria for Removal from the Study - Minocycline Trial Only 
Patients will be taken off symptom study drug/s if these values are met or exceeded:
10.21 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times 
the upper limit of normal. 
10.22 Total bilirubin > 3 times the upper limit of normal.
10.23 Signs and symptoms of severe rash (CTC v. 4 > grade 3) and hypersensitivity 
probably attributable to minocycline; if these appear, the study drug must be 
stopped immediately and the patient must be removed from the study.
10.24 Pregnancy during the study period.
10.25 The patient is permanently taken off chemotherapy treatment for any reason.
10.26 INR > 1.5; treating physician notified so that medical management occurs.
Symptom assessment measures will continue to be administered to patients taken off 
the study drugs until all planned assessments are completed.
11.0 Statistical considerations
11.1
Primary Analyses and Sample Size Justification
The primary outcome variable for the study is the average area under the curve (AUC) 
value of 5 symptoms: fatigue, drowsiness, pain, disturbed sleep, and lack of appetite 
over 2 weeks. These were the most prevalent and severe symptoms identified in our 
pilot studies of patients with pancreatic cancer.
Seventy-six patients will be randomized equally to the 2 treatment arms (minocycline 


2012-0587
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Page 21
and placebo).  To ensure that we have the same number of patients randomized 
between the treatment arms within chemotherapy treatment, the randomization will be 
stratified by chemotherapy treatment (i.e., FOLFIRINOX or gemcitabine-based 
chemotherapy). Note that this stratification allows for unequal numbers of patients being 
treated within each chemotherapy type. Taking into account a 10% attrition rate, we 
expect 68 evaluable patients. With 34 evaluable patients per treatment arm for 2 
weeks, we will be able to detect a 0.53 SD effect size on the average symptom AUC 
between the 2 treatments with 70% power and a one-tailed 5% significance test for 
primary outcome 1.1.  
Because this is a Phase II study with the intent of determining effect size estimates to 
inform a large clinical trial in the future, we chose a modest statistical power to detect a 
modest intervention effect of minocycline as a potential agent for reducing symptoms in 
cancer patients receiving chemotherapy. If the treatment has a more pronounced effect, 
it will be detected with higher power.
This study will allow us to obtain estimates of treatment effect and the variability of these 
estimates. We will test minocycline’s ability to reduce the severity of 5 symptoms. 
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, controlling for type of chemotherapy treatment. Estimates of 
treatment effect and between-subject variability will then be used to design a more 
comprehensive study for future clinical trials. We will also fit mixed models using the 
average of the 5 symptoms as the dependent variable, with time (week), group 
(minocycline vs. placebo), type of chemotherapy treatment, and other covariates as 
independent variables.  In addition, we will consider the subset of patients that have mild 
baseline symptoms and fit a linear regression model to compare the AUC values 
between minocycline and placebo. Further, we will fit a linear mixed model to the 
symptom scores to assess the effect of time, treatment, and other covariates.  To 
assess the effect of early dropout on the study results, we will perform sensitivity 
analyses and will consider statistical  methods such as LOCF (last observation carried 
forward) to model outcomes over time. Finally, because the number of assessment time 
points during the first cycle was increased after we had already enrolled patients, we 
will verify that the comparative results are similar for patients accrued before and after 
this change before combining the data for analysis. 
Non-Compliance with Study Agent: Patients who randomly do not comply with study 
agent dosing requirements will remain in the study under the intent-to-treat rule.
11.2
Secondary Analyses
To determine whether there was significant symptom reduction between symptom 
intervention arms after the first study chemotherapy cycle, we will compare the placebo 
and minocycline groups in terms of their change scores from the end of the first study 
cycle to the end of the last study cycle. We will also report the number of patients who 
have available symptom data at the end of cycle 2, cycle 3, and cycle 4, and account for 
drop-off driven by disease progression in the analysis. We expect to see better palliative 
effect in the minocycline group than in the placebo group, even in patients who remain 
in chemotherapy and are likely to be responders to disease control. 


2012-0587
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To address secondary objectives related to both the minocycline trial and the 
observational study, we will examine the relationship between dynamic changes in 
inflammation biomarkers and symptom outcomes, controlling for the grouping variable, 
disease progression (tumor markers, weight loss), evidence of infection, ECOG PS, 
age, and gender. Standard exploratory data analysis and descriptive statistics will be 
used.
Minocycline trial: In addition to testing the ability of minocycline to reduce the average 
AUC of the 5 selected symptoms, we will also perform a number of regression analyses 
to examine the relationship between AUC values/MDASI values and concentration 
serum of inflammatory markers. These analyses will include linear regression analyses 
of AUC values on the two measured CRP and IL-6 intensity values, as well as 
longitudinal analyses of the relationship between individual symptom scores as 
measured by MDASI, and CRP and IL-6 intensity variables. Using linear regression 
analyses, we will also examine the effects of minocycline treatment on each of the 
serum markers.
Observational arm: To understand the symptom profiles of these patients, we will 
produce Lowess curves for each symptom over time. We will fit mixed models using 
individual symptoms as dependent variables with patients treated as a random effect, 
and variables such as cancer stage, age, and gender as potential covariates. Also, with 
45 patients in this group, we will be able to estimate the prevalence of moderate to 
severe fatigue, a well-known symptom associated with FOLFIRINOX treatment (Conroy 
et al, 2011) within +/- 15% of the true fatigue prevalence with 95% confidence. This 
assumes a worst-case scenario in terms of largest variance possible for a proportion of 
50%.
12.0 References
Aronson, A. L. (1980). Pharmacotherapeutics of the newer tetracyclines. J Am Vet Med Assoc, 
176(10 Spec No), 1061-1068. PM:7216873.
Boyette-Davis J, Dougherty PM. Protection against oxaliplatin-induced mechanical hyperalgesia 
and intraepidermal nerve fiber loss by minocycline. Exp Neurol 229(2): 353-357, 6/2011.
Bruera E, Yennurajalingam S, Palmer JL, Perez-Cruz PE, Frisbee-Hume S, Allo JA, Williams 
JL, Cohen MZ. Methylphenidate and/or a nursing telephone intervention for fatigue in patients 
with advanced cancer: a randomized, placebo-controlled, phase II trial. J Clin Oncol. 2013 Jul 
1;31(19):2421-7. PM:23690414
Chen , J. & Huang, X. F. (2009). Interleukin-6 promotes carcinogenesis through multiple signal 
pathways. Comment on: Clinical significance of interleukin-6 gene polymorphism and IL-6 
serum level in pancreatic adenocarcinoma and chronic pancreatitis. Dig Dis Sci, 54(6), 
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