Clinical trial NCT01173692
Conditions: Oropharynx Cancer
Keywords: Oropharynx Cancer Radiation Therapy XRT Radiotherapy Minocycline Symptoms Head and Neck
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-07-22; Completion date: 2020-07-07
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if minocycline can reduce the symptoms reported by patients with oropharynx cancer, nasopharynx cancer, or unknown primary cancer of head and neck, who receive treatment with radiation therapy.

Detailed description:
The Study Drug:

Minocycline is an antibiotic and has been shown to interrupt cytokine production, which may help to reduce multiple symptoms.

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. Group 1 will take minocycline. Group 2 will take a placebo. A placebo is a substance that looks like the study drug but has no active ingredients.

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:

You will take the study drug/placebo, by mouth, every day for 7 weeks starting at the first week of radiation therapy. You may take the study drug/placebo with a full glass (8 ounces) of water. You may take it with or without food. 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 them. You should not lie down for at least 30 minutes after taking the study drug/placebo to prevent possible irritation of the inside of the esophagus, a known side effect. You will be given pamphlets with more information about how to take the study drug/placebo.

You will be given a daily diary to write down what time you take the study drug/placebo. You must bring the diary with you to every study visit for the study doctor and research staff to review.

You must bring the study drug/placebo container to every study visit.

Study Visits:

Before you start your radiation treatment:

* You will have blood (about 2 teaspoons) drawn to check your liver function, if this test has not been done in the last 3 months.
* If you are able to become pregnant, you will have a urine pregnancy test. The study staff will give you the pregnancy test kit, and will review and record the results of the test before you can pick up the study drug from the pharmacy. If you are pregnant, you will not be given the study drug.
* You will also complete 5 questionnaires about pain and other symptoms, your alcohol and tobacco history, your health status, and your quality of life. It should take about 15 minutes to complete all of the questionnaires.

During radiation treatment (approximately Weeks 1- 7 of radiation):

You will complete the symptom questionnaire in the clinic or by telephone 2 times a week. You will be asked about symptoms you may be experiencing and how they may be interfering with your normal daily activities. You will complete the symptom questionnaire during one of your regular clinic visits. If you do not have a clinic visit scheduled around the time that the questionnaire needs to be completed, a member of the study staff will call you at your home at a time that is convenient for you. The symptom questionnaire should take about 5 minutes to complete each time.

At about Week 4 of radiation, you will complete 4 additional questionnaires about pain and other symptoms, your tobacco use, and a quality of life questionnaire. It should take about 5 minutes to complete all of the questionnaires.

During the last week of radiation (about Week 6-7), you will complete 4 additional questionnaires about pain and other symptoms, your health status, and your quality of life. It should take about 10 minutes to complete all of the questionnaires.

Starting after the last week of radiation (about Weeks 7-10), the study staff will call you 2 times each week to check on you. This phone call should last about 5 minutes. If you have had several side effects from the radiation therapy, this phone call may take longer.

Follow-Up Phone Calls:

During Weeks 11-15, you will complete the pain and other symptoms questionnaire 1 time a week by phone. A member of the study staff will call you at your home at a time that is convenient for you. The symptom questionnaire should take about 5 minutes to complete by phone each time.

End of Study Visit:

Your last study visit will be the same day that you have your last clinic visit with the radiation doctor (around Weeks 13-15). At this visit, you will complete the pain and other symptoms questionnaire, your health status and the 2 smoking questionnaires. It should take about 5 minutes to complete both questionnaires.

Length of Study:

You will be on study for up to 15 weeks. You will take the study drug/placebo for up to 7 weeks and continue to complete the symptom survey until 15 weeks. You will be taken off study early if you experience intolerable side effects or the study doctor thinks it is in your best interest.

This is an investigational study. Minocycline is FDA approved and commercially available for the treatment of bacterial infection. Using minocycline for the treatment of the symptoms of radiation treatment for oropharynx cancer, nasopharynx cancer, or unknown primary cancer of head and neck, is investigational.

Up to 60 patients will take part in this research study. All will be enrolled at MD Anderson main campus as well as the regional care centers.

Arms: arm 1: Twice Daily Orally arm 2: 100 mg Twice Daily Orally
Interventions: intervention 1: Minocycline intervention 2: Placebo
Intervention descriptions: intervention 1: 100 mg twice daily (200 mg) by mouth , every day for 7 weeks starting first day of radiation therapy. intervention 2: Twice daily by mouth, every day for 7 weeks starting at first day of radiation therapy.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Page
Minocycline for reduction of radiation therapy treatment-related symptom burden in 
head and neck cancer: a randomized study.
2010-0096
Core Protocol Information
Short Title 
HNC
Study Chair: 
Gary B. Gunn
Additional Contact:
Angele K. Saleeba
Araceli G. Garcia-Gonzalez
Toni Williams
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
Araceli G. Garcia-Gonzalez
Loretta A. Williams
OPR DSMB
PDOL OPR DMC Addl Cont
Study Staff Recipients
None
Department:
Symptom Research
Phone:
713-745-3470
Unit:
1450
Study Manager:
Araceli G. Garcia-Gonzalez
Full Title: 
Minocycline for reduction of radiation therapy treatment-
related symptom burden in head and neck cancer: a 
randomized study.
Public Description:
N/A
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 08/28/2019
Version:
15
Document Status:
Saved as "Final"
Submitted by:
Angele K. Saleeba--8/28/2019 8:51:48 AM
OPR Action:
Accepted by:  Melinda E. Gordon -- 8/28/2019 9:47:45 AM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
1.0 Objectives
The primary objective of this protocol is to test the efficacy of minocycline in reducing multiple patient-reported symptoms in patients with oropharyngeal 
cancer, nasopharyngeal cancer, or unknown primary cancer of head and neck treated with definitive radiation therapy.
2.0 Rationale
The study aims to test a symptom-reduction strategy based on underlying symptom mechanisms associated with cancer treatments. Using a blinded, 
randomized placebo-controlled trial, we will evaluate minocycline safety and ability to reduce the symptom burden of oropharyngeal cancer, 
nasopharyngeal cancer, or unknown primary cancer of head and neck treated with radiation therapy. The significance of this research is that it (a) 
evaluates a low-toxicity, low-cost symptom therapy, (b) evaluates a therapy which could reduce multiple commonly reported symptoms in oropharyngeal 
cancer, nasopharyngeal cancer, or unknown primary cancer of head and neck, and (c) seeks to establish simple medical symptom prevention therapy for 
a disease site and treatment for which the symptom burden is high and few medical symptom prevention strategies exist.
The agent tested in this trial is minocycline.  The target of action for the proposed intervention is in reduction of proinflammatory cytokines, specifically 
IL-1, IL-6, and TNF-alpha, likely mediators of multiple symptom expression.  Minocycline also crosses the blood-brain barrier, possibly reducing 
inflammation in the central nervous system, potentially reducing multiple symptom expression at the brain level.
3.0 Background
Cancer was diagnosed in more than 1.4 million people in the United States in 2007 alone — 34,360 with head and neck cancer (HNC) (Jemal et al., 
2007).  Many of these patients received aggressive therapy and experienced multiple symptoms that cause them significant distress and impair function 
and rehabilitation. Whereas many of these symptoms are the result of disease, it is increasingly recognized that pain, fatigue, sleep disturbance, cognitive 
dysfunction, and affective symptoms can also be caused by cancer treatment. Treatment-related symptoms can directly affect survival if they become so 
severe that patients abandon potentially curative therapies (Borden & Parkinson, 1998; Jeremic et al., 2003). Moreover, treatment-related symptoms may 
persist for weeks, months, or years and may worsen, even if the cancer improves.
There is growing awareness that common biologic mechanisms may cause or contribute to some of these clusters of symptoms at the same time 
(Barsevick et al., 2006; Dodd et al., 2005; Wang et al., 2006). The theoretical underpinning for the proposed studies, based on the animal model of 
inflammation-induced sickness behavior, is that dysregulated inflammation and its downstream toxic effects represent a significant biologic basis for 
subjectively reported clusters of symptoms (Cleeland et al., 2003; Lee et al., 2004). Based on this model, optimal symptomatic control would attack both 
underlying symptom mechanisms as well as the end effects of these mechanisms with symptom-focused therapies. 
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 radiotherapy and chemotherapy, increases production of inflammatory cytokines, especially interleukin (IL)-6 and tumor necrosis factor (TNF) 
variants (Linard et al., 2004; Linard et al., 2005).  Inflammatory reaction is a classic feature of radiation exposure, and animal models have shown an 
increase in IL-6 several days after such exposure (Van der Meeren et al., 2003). This increase in inflammation is a prime candidate for the mechanism 
behind increases in treatment-related symptoms. It has been suggested that reduction of this treatment-induced inflammatory response might significantly 
reduce the morbidity associated with radiotherapy (Garden, 2003).
3.1  Symptom Management
The control or prevention of cancer-related cytokine dysregulation presents new opportunities for symptom reduction or prevention. Thus, a goal of the 
proposed study is the development of symptom-management strategy 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. First, 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. Special difficulties include the poor fit of current disease models of research for implementing this kind of health-related investigation and lack of 
statistical models that integrate “rough” self-report data and biologic data (Cleeland, 2001). However, patient-reported outcome research has recently 
been promoted by the U.S. Food and Drug Administration (FDA) for more accurate therapeutic agent evaluation, and symptom reduction has been 
recognized as a primary clinical benefit for drug approval (FDA, 2006b).
Other barriers have hindered development of evidence-based methods for controlling treatment-related symptom burden, despite the availability of more 
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. 
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 typically prescribe multiple agents based on anecdotal experience or the patient’s perceived needs, 
rather than on evidence-based research (Foley et al., 2001).
3.2 Head and Neck Cancer Treatment Side-Effects
All cancer therapies, especially multimodality and multiagent treatment programs are associated with a spectrum of early and late adverse effects. 
Because of the wide variety of symptoms and their severity, toxicity data is a further challenge to evaluate. One recent analysis noted an almost 500% 
increase in the number of early toxicity events with chemoradiation as compared with standard postoperative radiotherapy for head and neck cancers 
(Trotti et al., 2007). Chemoradiotherapy for head and neck cancers has consistently shown to yield clinically relevant improvement in locoregional control 
and overall survival, though at the cost of more severe early toxicity (Pignon et al., 2000). However, many patients treated with radiation therapy alone still 
report high symptom burden. Early effects are typically expressed during or within a few weeks after the end of therapy, typically in proliferative tissues 
and organs such as the skin, the mucosal lining of the GI tract and the hematopoietic system. The alterations in swallowing and nutritional intake may 
cause poor compliance to therapy, may have long-term effects and even cause death of the patient.  The burden of treatment- related adverse effects 
needs to be well documented and controlled to improve both physical and social functioning in these patients. Thus, a goal of the proposed study is to 
develop symptom management strategy to improve patient outcomes and also to improve compliance to intensive treatment regimen, in this case 
definitive radiation therapy.
4.0 Background Drug Information
4.1  Minocycline hydrochloride (Minocin®, manufactured by Triaxc Pharmaceuticals, LLC) 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. 
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-alpha, IL-1b 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 lipopoly-saccharide 
administration in animals (Yamaki et al., 1998). Minocycline was found to decrease IL-6 and the acute-phase response protein C-reactive protein (CRP) 
levels in patients with rheumatoid arthritis (Kloppenburg et al., 1996).
Commonly associated side effects include light-headedness, vestibular symptoms, headache, and nausea (Gump et al., 1977), with no correlation seen 
between serum concentration and toxicity (Kloppenburg et al., 1995). Minocycline is now widely used in the management of dermatitis associated with 
targeted therapy in cancer.


4.2  Absolute Contraindications to study symptom intervention agent Minocycline 
4.21  hypersensitivity to any tetracyclines;
4.22  pregnancy
      4.23  hepatotoxicity (aspartate aminotransferase (AST) or alanine aminotransferase (ALT); 2 times the upper limit of normal)
4.3 Minocycline Common Adverse Reactions
4.31  Minocycline: Dizziness (9%) and vertigo.
4.4 Minocycline Monitoring Parameters
4.41
Minocycline: LFTs, BUN, Sr Cr, 
4.42
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.
4.44
Minocycline Drug Interactions
4.441
Minocycline
4.442
Calcium-, magnesium-, or aluminum-containing antacids, bile acid sequestrants, bismuth, oral contraceptives, iron, zinc, sodium 
bicarbonate, penicillins, quinapril may decrease absorption of minocycline:  Avoid taking within 2 hours of using this medication.
4.443
Methoxyflurane anesthesia, when concurrent with minocycline, may cause fatal nephrotoxicity. 
4.444
Retinoic acid derivatives: May increase risk of pseudotumor cerebri.
4.445
Warfarin: Hypoprothrombinemic response may be increased with tetracyclines; monitor INR closely during initiation or 
discontinuation
4.45
Storage Information
4.451  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
5.0 Study Design
Using a blinded, randomized placebo-controlled trial, we will evaluate minocycline safety and ability to reduce the symptom burden of oropharyngeal 
cancer, nasopharyngeal cancer, or unknown primary cancer of head and neck treated with radiation therapy. This is especially important in trials where 
symptom reduction is the outcome and where knowledge of the treatment arm might bias assessment staff or patient.  The compounding pharmacy will 
prepare the appropriate active agent and placebo for each patient.
Design:  Phase II blinded, randomized placebo-controlled trial
Symptom Intervention Agent: minocycline
Study Period:  15 weeks: intervention agent daily during radiation for 7 weeks (+/- 5 days) + additional follow-up to first follow up (4-8 weeks) for a total 
of 11-15 weeks. 
Primary Outcome Variable: 7-week (+/- 5 days) area under the curve (AUC) for select MDASI-HNC symptoms namely fatigue, pain, sleep disturbance, 
difficulty swallowing and lack of appetite.
Forty patients will be randomized to either minocycline or placebo, twenty in each arm. AUC values for patients who drop out of the study after entering 
two weeks of AUC data will be included by carrying their last symptom data forward for the remaining study period under the intent to treat rule (ITT).  The 
carry-forward method of handling drop-outs will be revisited upon completion of the study to determine if adjustments to these values can be made using 
longitudinal regression models estimated from patients who completed the entire study. 
All Grade 3 and 4 toxicities reported by patients in this trial will be evaluated by the principal investigator and treating physician, or other attending 
physician if PI is not available, to determine if the toxicities were due to study medication.  We will use standard 3+3 criteria for determining whether 
treatment exceeds either grade 3 or 4 toxicities for the first 6 patients assigned to minocycline.  That is, if more than 1 symptom intervention related 
toxicity (grade 3, 4) in the first 6 patients assigned to minocycline is observed, the study will be terminated.  
A list of adverse events known to be associated with primary treatment is listed in section 4.0 of the protocol.
The determination of whether a toxicity (grade 3, 4) was due to minocycline received by the patient (rather than the primary radiation) will be performed by 
the principal investigator in consultation with the treating physician. 
The interaction screening will be the responsibility of the research staff. The Research staff will review any current or new medications started with the 
patient prior to initiating treatment. During the trial, the research staff will capture all drug interactions causing an adverse event on the Adverse Event 
forms. We plan to document all medications patients will be or have been using during the trial.  Medication sheets will be provided to both patients and 
treating physicians to inform them of the possibility that the patients may be on this drug (see Appendices T and TT).  
Minocycline will begin at the start of radiation therapy and continue daily through the final radiation treatment day.
6.0 Administration of Pharmacologic Agent
As stated in section 5, preparation of symptom intervention medication for each patient will be done by the compounding pharmacy. Patients will pick up 
the assigned study medications at one of the outpatient pharmacy stations in M. D. Anderson.  At pickup patients will receive instruction in how to take 
study medications. 
The participants will take study medication twice daily, starting on day one of radiation therapy. The final day of study medication will be the 
final day of radiation therapy.  The participants will take study medications twice daily during entire course of radiation therapy, including weekend 
days. 
Patients will be asked to bring their study medication container to the clinic where study staff will perform a capsule count  each week during one of their 
radiation weekly appointments. Results of the capsule count will be recorded on the Study Medication Accountability form.
Unused drugs will be returned to Investigational Pharmacy Services by the study staff, or destroyed in a red biohazard bag.  Once the capsule count is 
completed, the capsules can be placed into the M. D. Anderson biohazard waste system.
 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 radiation)
Initial Dose (starts on 
first day of radiation)


Minocycline
100mg capsules
100mg two times a day 
(200 mg)
Matching placebo
7.0 Data Collection Tools
Patient Reported Outcome (PRO) Measurements
7.11  Symptom Measurement  Symptom data will be collected using the MDASI- HNC module of the M. D. Anderson Symptom Inventory (see Appendix 
C and Appendix P). MDASI-HNC items namely fatigue, pain, sleep disturbance, difficulty swallowing and lack of appetite will be used to calculate the 
symptom AUC. Prior studies (Rosenthal, et al, 2007, 2008) have indicated that a significant proportion of patients reported these symptoms to be 
moderate to severe. The MDASI-HNC will be collected face to face in the clinic, through an interactive voice response system, through a tablet PC, 
through phone calls by field coordinators, or by regular mail to measure symptom burden over time of the treatment and post treatment. 
7.12  Measure of Quality of Life  The EuroQol (EQ-5D) is a standardized instrument for use as a measure of health outcome.  (See Appendix 
D)  Applicable to a wide range of health conditions and treatments, it provides a simple descriptive profile and a single index value for health status. 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 five 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. 
7.13  Measure of Global Quality of Life  The Global Quality of Life (GQL) is a single item asking patients to rate their quality of life on a 0 to 10 scale 
over the past week. (See Appendix DD). 
7.14  Measure of Patient Satisfaction with Study Medication Scale   The Study Medication Satisfaction Scale is a short, 7-item scale that asks 
patients about several areas of satisfaction. (See Appendix E)  The scale includes questions about ease or difficulty of taking the medication in general 
and in its current form, convenience of taking the study medication as instructed, and patient confidence that the study medication is of benefit.  
7.15 a Tobacco History Form The Tobacco History Form is a short questionnaire that asks about smoking history. (See Appendix F).  
7.15 b Follow-Up Smoking Assessment Form  The Follow-Up Smoking Assessment Form asks three questions about smoking subsequent to the start 
of radiation therapy (See Appendix FF).  
7.16 Alcohol History Form The Alcohol History Form is a short questionnaire that asks about alcohol history at baseline. (See Appendix G).
7.2 Case Report Forms (CRFs)
7.21 Demographic Form  This form includes patient birth date, gender, marital status, race, ethnicity, education, and employment status. (See Appendix 
H)  The Demographic Form will be completed at baseline.
7.22  Charlson Comorbidity Index  The Charlson Comorbidity Index yields a comorbidity score, to control for serious concurrent chronic disease 
conditions (Charlson et al., 1994) (Appendix I).
 
7.23  On-Study Form  The On-Study Form contains data about disease, previous treatment, whether a patient is on concurrent protocols (See Appendix 
J). This form will be completed at baseline.
7.24  Clinical Monitoring Form  The Clinical Monitoring Form contains clinical data including Body Mass Index (BMI), blood pressure, performance 
status, symptom treatment, and CTC toxicity scores. (See Appendix K).
7.25  Medication Form  The Medication Form contains data about types of medications patients have been prescribed.  Medication types include pain 
medications, antiemetics, and psychotropics among others. There is also a general section for other types of medications patients may be taking. (See 
Appendix L).
7.26  Daily Tracking of Study Medication Taken by Participants  Patients will be given a diary and asked to record their doses of study medication 
(see Appendix M).   Each page of the diary contains space to document 7 days of study medication consumption.  Patients will be asked to record the 
number of study capsules they take at one time and also check off the time slot when the capsules are ingested.  
7.27  Study Medication Accountability Form  This form contains study medication data including the number of capsules dispensed to the patient at 
the last visit to the outpatient pharmacy, how many capsules were returned from the last visit, and the number of days the pills were taken. (See Appendix 
N). 
7.28  Laboratory Data Form  The Laboratory Data Form contains data from blood analysis including 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).  (See Appendix W). These values will be recorded if they are available in the patient medical record from 
a blood draw performed for clinical purposes. 
Note: Liver function tests are required at baseline. If they were not performed within the past 3 months prior to starting treatment with the symptom drug/ 
placebo, they will be drawn for eligibility purposes.
 
7.29 Treatment Summary Form  The Treatment Summary Form contains data about radiation treatment received and induction chemotherapy. (See 
Appendix O).
7.30 Final Study Status Form  The Final Study Status Form contains data about patient disposition at the end of the study (i.e., completed study, 
withdrew, vital status) and tumor evaluation after treatment. (See Appendix OO).
7.31 CTC Toxicity Form  The CTC Toxicity Score Form contains the maximum toxicity score in the last seven days, or since the last assessment.  (See 
Appendix X).
8.0 Patient Eligibility
Patient Eligibility
  8.11 Inclusion Criteria


8.111 
Patients with a pathologically proven diagnosis of oropharyngeal cancer, nasopharyngeal cancer, or unknown primary cancer of head and 
neck in MDACC receiving radiation therapy with or without induction chemotherapy. 
8.112 
Patients > 18 years old.
8.113
Patients with the above cancers, T0, TX, T1 to T3, N any, M0 receiving IMRT (to unilateral or bilateral neck), 64-72 Gy in 6-7 weeks as 
definitive treatment.
8.114 
Patients must have normal renal function test and no prior renal disease: The screening cut off for serum creatinine < upper limit of normal.  
8.115 
Patients must have normal hepatic function test and no prior liver disease:  The screening results for total bilirubin must be < 1.5 times the 
upper limit of normal. The screening results for the following must be < 2 times the upper limit of normal for patients to be eligible: Alkaline phosphatase 
(ALP) and Alanine aminotransferase (ALT).  The screening results for Aspartate aminotransferase (AST) must be < 2 times the upper limit of normal if 
available.
8.116
Patients who speak English (due to the novel research and its complexity, we are only accruing English speaking patients to the protocol).
8.117
Patients must be willing to discontinue taking dong quai and/or St John's wort.
8.118
Patients must be willing and able to review, understand, and provide written consent.
  8.12  Exclusion Criteria               
8.121
Patients receiving concurrent chemotherapy or concurrent biologic agent. 
8.122
Patients who are taking medications or have conditions that potentially preclude use of the study medication or intervention as determined by 
the treating physician.
8.123
Patients who are enrolled in another symptom management trial or receiving active treatment under another clinical trial.
8.124
Bile duct obstruction or cholelithiasis.
8.125 
History of clinically significant cutaneous drug reaction, or a history of clinically significant hypersensitivity reaction, including multiple allergies 
or drug reaction.
8.126  Pre-existing psychosis or bipolar disorder.
8.127 Hypersensitivity to any tetracyclines.
8.128 Patients on anticoagulants (ie warfarin/heparin).
     
8.129 Patients with INR > 1.5.
8.130 Patients taking any tetracycline within the last 15 days.
8.131 Patients that are pregnant. 
8.132 Patients treated with upfront radical surgery at the primary site (other than diagnostic tonsillectomy or excision).
9.0 Patient Enrollment and Registration
Patient Enrollment
Patients will be screened for eligibility and recruited for enrollment in the outpatient Head and Neck Cancer Clinic in Radiation Oncology before their 
radiation therapy starts.  Enrollment will also take place in the outpatient radiation oncology facilities at the MD Anderson regional care centers: Sugar 
Land, Katy, Bay Area, and the Woodlands.
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/authorization. 
Women of child-bearing potential who want to participate will be told that we will perform a mandatory pregnancy screening test through a urine sample at 
baseline. Study staff will provide the pregnancy kits to these women and make sure the results are known and recorded in the follow-up notes in Clinic 
Station before additional study drug prescriptions are filled by the Investigational Pharmacy. If the pregnancy test is positive the patient will not be 
prescribed the symptom drug study.
At enrollment patients will be informed that they will receive a stipend in the total amount of $60 for participation in the pilot study.  The stipend will be 
distributed in $20 increments at three times during the study.  Stipends will be distributed to participants at weeks 1, 7 (+/- one week), and at the final 
study follow up visit.
Enrolled patients will be registered into the Clinical Oncology Research System (CORe), the institutional patient data management system.
Patient Randomization and Assignment to Treatment Arm 
The study will accrue a total of 40 patients with 20 patients each in the placebo and minocycline group. Prior to accruing the first patient, a 
randomization list will be generated by our biostatistician collaborator from the Department of Biostatistics for all 40 patients stating which group a 
patient was randomized. This list containing the accrual number and treatment group information will be given to Investigational Pharmacy. A sealed 
backup list will be kept by the assigned data analyst at the Department of Symptom Research. This list will only be opened in case unblinding is 
needed.
Recruitment efforts will be made such that patients with induction chemotherapy and/or unilateral neck radiation comprised at least 20% of 
the sample.
Once a patient is enrolled the study staff will contact  the Investigational Pharmacy and let them know of the patient's accrual number and patient ID. 
Investigational Pharmacy retrieves the randomized treatment arm information from the generated randomization list.  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 be randomized into one of the 2 possible arms.  (See Section 5.0 Study Design).
10.0 Assessment Schedule
Please see Appendix P for an expanded study assessment/evaluation schedule.
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. 
When all analysis has been completed and all study results have been reported, the electronic and paper files will be stored in a password-protected MD 
Anderson secure server. This stored data may be made available to MD Anderson research and clinical faculty for research purposes, with appropriate 
validation and access controls, so it can facilitate research cross-fertilization and speed insight discovery. Patient data also will be stored and accessible 
in the MD Anderson Translational Research Accelerator database (TRA; PI: A. Futreal). 
11.0 Adverse Event Reporting
11.1 Adverse Events (AE)  (See Appendix Q)
All patients will be seen weekly during radiation therapy in the radiation oncology clinics, allowing for close monitoring of potential adverse events by clinic 
and research staff during treatment. 
During the 3 weeks post radiation, patients will be monitored through weekly phone calls by the research staff, and then every other week for another 3 
weeks. 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 weeks 1, 4, 7, and end of study. 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. (See 
Appendix R)
Grade 1 and Grade 2 AEs based on radiation treatment and symptom treatment that are expected or unrelated will not be reported.  AEs that are Grade 3 
and above that are definite, probable, or possible and related will be reported.  AEs will be tabulated and reported as a summary on the continuing review 
report. All Grade 3 and 4 toxicities reported by patients in this trial will be evaluated by the principal investigator and treating physician to determine if the 
toxicities were due to study medication.  
11.2  Serious Adverse Events (SAE)  (See Appendix S)
A serious adverse event is any adverse drug experience occurring at any dose that results in any of the following outcomes: 
Death
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.
Inpatient hospitalization or prolongation of existing hospitalization
A persistent or significant disability/incapacity – a substantial disruption of a person’s ability to conduct normal life functions.
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 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).
Important medical events as defined above, may also be considered serious adverse events.  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.
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 M. D. 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 Clinical Research Support Center, 
regardless of attribution (within 5 working days of knowledge of the event). 
All life-threatening or fatal events, expected or unexpected, and regardless of attribution to the study drug, must have a written report submitted 
within 24 hours (next working day) of knowledge of the event to the Safety Project Manager in the Clinical Research Support Center.
The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for reporting to the Clinical Research Support Center. 
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 have returned to baseline, progression of the event has 
stabilized, or there has been acceptable resolution of the event.
·
Additionally, any serious adverse events that occur after the 30 day time period that are related to the study treatment must be reported 
to the Clinical Research Support Center. This may include the development of a secondary malignancy.
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.
12.0 Criteria for Removal from the Study
12.1
Patients will be taken off study if these values are met or exceeded:
12.11 
Alkaline phosphatase (ALP) is >2 times the upper limit of normal 
12.12
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is >2 times the upper limit of normal 
12.13
Total bilirubin > 1.5 times the upper limit of normal
12.14
Monitor for signs and symptoms of severe rash (CTC version 4  > grade 3), hypersensitivity, and if appear, need to stop drug immediately 
and discontinue study.
12.15
Pregnancy during the study period
12.16
INR > 1.5.  Treating physician notified so that medical management occurs.
13.0 Statistical Analysis Plan
13.1
Sample Size and Randomization
Forty patients will be randomized equally to the two treatment arms - minocycline and placebo. With 20 patients per treatment arm, we will be able to 
detect a 0.70 SD effect size on the symptom AUC between the two treatments with 70% power and one-sided 5% significance test. Because this is a 
pilot study with the intent of providing effect size estimates to inform large clinical trial in the future, we chose a modest statistical power.  
13.2
Analysis Plan
Our emphasis is to test the efficacy of minocycline as a potential agent in reducing patient-reported symptoms in cancer patients receiving radiation 
therapy. The proposed phase II clinical-trial for screening potentially effective symptom intervention agent will provide moderate power in detecting 
modest intervention effect.  If the treatment has a more pronounced effect, then it will be detected with higher power.  
This study will allow us to obtain estimates of treatment effect and the variability of these estimates. Estimates of treatment effect will be obtained using 
standard linear regression techniques in which AUC values (lc(i)) are regressed on indicator variables that represent treatment received.  Estimates of 
treatment effect and between subject variability will then be used to design a more comprehensive study in future clinical trials.     
Recruitment efforts will be made such that patients with induction chemotherapy and/or unilateral neck comprised at least 20% of the sample. Indicator 
variables for the type of treatment (induction chemotherapy  vs. radiation therapy alone) and location (unilateral neck vs. bilateral neck) will be created. In 
addition to the formal evaluation of treatment effects on the primary outcome, we will also examine the prognostic effects of the type of treatment, 
location, disease stage, ECOG status, age and gender in predicting the outcome variable.  Standard exploratory data analysis techniques and descriptive 
statistics will be used.
We will test minocycline in its ability to reduce values of 5 symptoms. Assuming that patients accrue at the rate of 4 per month, we anticipate that this pilot 
study will require approximately 14 months to complete. 
We will need at least 2 weeks of treatment with the study drug/placebo for patients to be considered as evaluable.  Any patient who drops out prior to this 
will be replaced. 
13.21  Primary Outcome Variable


The primary outcome variable will be the combined AUC for selected symptoms. The value of this variable for patient i is denoted lc(i) and is comprised of 
the MDASI-HNC scores for fatigue, pain, sleep disturbance, difficulty swallowing and lack of appetite collected during the 7 weeks of RadTx. 
Because lc(i) represent the average of a large number of ordinal variables, we assume by the central limit theorem that its value can be considered to be 
approximately normally distributed. 
13.22  Secondary Outcome
In addition to obtaining estimate of treatment effect, this protocol also aims to pilot the procedure used in calculating area under the curve (AUC). 
Because future clinical trial requires frequent monitoring and updating of symptom data collected using either  the interactive voice response system 
or  paper and pencil, the logistics developed here will be useful in ensuring an efficient data collection system.
We are also interested in exploring predictors of survival. Univariate Cox proportional hazards models will be used to screen for potential predictors 
(demographic and clinical variables) of overall survival. Predictors that are significant with  p<.10 will be included in the multivariate Cox proportional 
hazards models. Final predictors will be selected by stepwise regression, with an entry level of 0.1 and a stay level of 0.05. Standard model fitting 
diagnostics will be performed. Finally, Cox survival curves will be plotted.
13.23 Non-Compliance with Study Agent
Patients who do not comply with study agent dosing requirements will remain in the study under the intent to treat rule.
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