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13.1 sample size/accrual rate

Given the relative frequencies of mutationsit is anticipated that we will need to enroll up to 100 patients until we have 30 evaluable patients on each open agent cohort. Once all sites are open, we hope to accrue 150-200 patients a year. It is anticipated that accrual will require at least 1.5 - 3 years.
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13.2 analysis of additional endpoints

All molecular and other secondary evaluations will be considered for exploratory analyses. In general, it is anticipated that non-parametric analyses will be used for these evaluations. In view of the exploratory nature of these analyses, any p-values reported will not be adjusted for multiple comparisons, and any such analyses will be stated carefully as being hypothesisgenerating. All eligible patients who have initiated treatment will be included in the toxicity assessments.
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14. human subjects protections 14.1

This study will be open to all individuals regardless of gender, ethnicity, or race provided that the aforementioned inclusion and exclusion criteria are met. For safety reasons, pregnant women and children are excluded from this study. Patients for this study will be recruited through internal referral, our physician referral base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer). Participants should realize that there is no guarantee of benefit to them from participation in this trial. The results of this trial may benefit future cancer patients. To date, there is no information that suggests that differences in drug metabolism or effect on tumor would be expected in one ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but a balance must be struck between participant safety considerations and limitations on the number of individuals exposed to potentially ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to ethnic identity are noted, a follow-up study may be written to investigate those differences more fully.
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14.1.1 inclusion of women and

| Accrual Targets Ethnic Category           | Sex/Gender   |           |                         |    |          |     |     |
|-------------------------------------------|--------------|-----------|-------------------------|----|----------|-----|-----|
| Females                                   | Males        | Total     |                         |    |          |     |     |
| Hispanic or Latino                        | 18           | 18        | 36                      |    |          |     |     |
| Not Hispanic or Latino                    | 72           | 72        | 144                     |    |          |     |     |
| Ethnic Category: Total of all subjects    | 90 (A1)      | +         | 90 (B1)                 | =  | 180 (C1) |     |     |
| Racial Category                           |              |           |                         |    |          |     |     |
| American Indian or Alaskan Native         | 1            | 1         | 2                       |    |          |     |     |
| Asian                                     | 8            | 8         | 16                      |    |          |     |     |
| Black or African American                 | 8            | 8         | 16                      |    |          |     |     |
| Native Hawaiian or other Pacific Islander | 1            | 1         | 2                       |    |          |     |     |
| White                                     | 72           | 72        | 144                     |    |          |     |     |
| Racial Category: Total of all subjects    | 90 (A2)      | +         | 90 (B2)                 | =  | 180 (C2) |     |     |
| (A1 = A2)                                 | (B1 = B2)    | (C1 = C2) |                         |    |          |     |     |
| Accrual Rate:                             | 2-3          | pts/month | Total Expected Accrual: | 45 | Min      | 700 | Max |
| Projected Start Date of study:            | 10/20/12     |           |                         |    |          |     |     |  
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the aforementioned inclusion and exclusion criteria are met.
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14.2 justification for exclusions

Because the effects of study investigational agents on the developing human fetus are unknown, pregnant women will be excluded from this trial. Nursing women are also excluded, as there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with study medications. Participants with unstable or serious medical conditions (ongoing or active infection, symptomatic congestive heart failure [AHA Class II or worse], unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements) are excluded due to the possibility that the underlying condition may obscure the attribution of effect and adverse events with respect to study drugs and may limit study compliance.
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14.2.1 participation of children

Because no dosing or adverse event data are currently available on the use of many of these investigational agents in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric Phase I/II trials.
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14.3 evaluation of benefits and

There may or may not be any clinical benefit to a patient from participation in this trial. Their participation will benefit future cancer patients. Potential risks include the possible occurrence of any of a range of side effects that are listed in the consent document, as well as the risks associated with the acquisition and disclosure of information about germline variants relevant to a patient's hereditary risk of disease. The procedure for protecting against or minimizing risks will be to medically evaluate patients as described in the Study Calendar (Section 10). To minimize the risk of disclosing information about potential nonambiguous germline variants from whole exome sequencing, samples will be de-identified once the patient has completed treatment and is taken off study. No genetic data will be shared with the patient other than the data from the targeted sequencing panel. A Certificate of Confidentiality has been obtained for this study. The research component of this study (2 CT tumor biopsies, with the possibility of a third optional biopsy should a baseline tumor biopsy sample contain insufficient DNA) confers radiation exposure at an effective dose of 1.6 rem at the NIH Clinical Center. This dose is below NIH RSC guidelines for adults of 5.0 rem per year and represents a slightly greater than minimal risk to patients.
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14.4 consent and assent process

This protocol includes separate informed consent forms for tumor biopsy collection and treatment. An associate or principal investigator on the trial will inform patients of the purpose, alternatives, drug administration plan, research objectives, and follow-up of this trial. The patient will be provided IRB-approved consent(s) for review and signature and his/her questions will be answered. After a decision is made to enroll into the study, a signature will be obtained from the patient. The original signed consent(s) go to Medical Records; a copy is placed in the research record. All patients must have a signed informed consent form and an on-study (confirmation of eligibility) form filled out and signed by a participating investigator before entering on study.
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14.5 procedure for protecting against

All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. This study may involve risks to patients, which are currently unforeseeable. All patients will be monitored for side effects from taking study medication and from undergoing blood sampling procedures. If patients suffer any physical injury as a result of the participation in this study at the NCI, immediate medical treatment is available at the Clinical Center, National Cancer Institute, Bethesda, Maryland. Although no compensation is available, any injury will be evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
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| Karnofsky Performance Scale   |                                                                                 |
|-------------------------------|---------------------------------------------------------------------------------|
| Percent                       | Description                                                                     |
| 100                           | Normal, no complaints, no evidence of disease.                                  |
| 90                            | Able to carry on normal activity; minor signs or  symptoms of disease.          |
| 80                            | Normal activity with effort; some signs or symptoms of  disease.                |
| 70                            | Cares for self, unable to carry on normal activity or to  do active work.       |
| 60                            | Requires occasional assistance, but is able to care for  most of his/her needs. |
| 50                            | Requires considerable assistance and frequent medical  care.                    |
| 40                            | Disabled, requires special care and assistance.                                 |
| 30                            | Severely disabled, hospitalization indicated. Death not  imminent.              |
| 20                            | Very sick, hospitalization indicated. Death not  imminent.                      |
| 10                            | Moribund, fatal processes progressing rapidly.                                  |
| 0                             | Dead.                                                                           |
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appendix b potential drug interactions

| CYP2C19 Inhibitors Amiodarone Amitriptyline Amprenavir Aprepitant Azelastine Bortezomib Buprenorphine Cholecalciferol/Vitamin D3 Cimetidine Citalopram Clotrimazole Clozapine Delavirdine Diazepam Dimethyl sulfoxide Drospirenone Efavirenz Entacapone Ethinyl estradiol Ethotoin                                                                                                                                                                                  | Felbamate Fenofibrate Fluconazole Fluoxetine Fluvoxamine Fosamprenavir Gefitinib Gemfibrozil Imipramine Indinavir Indomethacin Isoniazid Ketoconazole Lansoprazole Letrozole Loratadine Losartan Mephobarbital Mestranol Methimazole   | Methoxsalen Methsuximide Miconazole Moclobemide Modafinil Nelfinavir Nicardipine Nilutamide Olanzapine Omeprazole Orphenadrine Oxcarbazepine Paroxetine Pentamidine Pimozide Pioglitazone Probenecid Progesterone Propofol Rabeprazole   | Ritonavir Rosiglitazone Saquinavir Selegiline Sertraline Sildenafil Sulconazole Telmisartan Ticlopidine Tioconazole Topiramate Torsemide Tranylcypromine Valdecoxib Valproic acid Voriconazole Warfarin Zafirlukast   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CYP2C19 Inducers Aminoglutethimide                                                                                                                                                                                                                                                                                                                                                                                                                                  | Fosphenytoin                                                                                                                                                                                                                           | Rifampin                                                                                                                                                                                                                                 | St. John's wort                                                                                                                                                                                                       |
| Carbamazepine                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Phenytoin                                                                                                                                                                                                                              |                                                                                                                                                                                                                                          |                                                                                                                                                                                                                       |
| CYP2C19 Substrates Carisoprodol Cilostazol Citalopram Clobazam Clomipramine Desogestrel Diazepam                                                                                                                                                                                                                                                                                                                                                                    | Escitalopram  Esomeprazole  Fosphenytoin Imipramine Lansoprazole Mephenytoin Mephobarbital                                                                                                                                             | Methsuximide Moclobemide  Nelfinavir  Nilutamide Omeprazole Pantoprazole Pentamidine                                                                                                                                                     | Phenobarbital Phenytoin Progesterone  Rabeprazole Sertraline Trimipramine Voriconazole                                                                                                                                |
| CYP3A4 Inhibitors Acetaminophen Acetazolamide Amiodarone Amlodipine Amprenavir Anastrozole Aprepitant Atazanavir Atorvastatin Azelastine Azithromycin Betamethasone Bortezomib Bromocriptine Caffeine Cerivastatin Chloramphenicol Chlorzoxazone Cyclosporine Danazol Dasatinib  Delavirdine Desipramine Dexmedetomidine Diazepam  Diclofenac  Dihydroergotamine  Diltiazem Disulfiram Docetaxel Doxorubicin Doxycycline Drospirenone Efavirenz Enoxacin Entacapone | Glyburide Grapefruit juice  Haloperidol Hydralazine Ifosfamide Imatinib Indinavir Irbesartan Isoniazid Isradipine Itraconazole Ketoconazole Lansoprazole Lidocaine  Lomustine Losartan  Lovastatin Mefloquine                          | Modafinil Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nisoldipine Nizatidine Norfloxacin Olanzapine Omeprazole Orphenadrine Oxybutynin Paroxetine Pentamidine Pergolide Phencyclidine Pilocarpine                            | Ranolazine Risperidone Ritonavir Saquinavir Selegiline Sertraline Sildenafil Sirolimus Sulconazole Tacrolimus Tamoxifen Telithromycin Teniposide Testosterone Tetracycline Ticlopidine Tranylcypromine Trazodone      |
| 107                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                          |                                                                                                                                                                                                                       |  
| Cimetidine Ciprofloxacin Cisapride Clarithromycin Clemastine Clofazimine Clotrimazole Clozapine Cocaine Conivaptan Cyclophosphamide                                                                                                                                                                                                                                                                                                                                            | Ergotamine Erythromycin Ethinyl estradiol Etoposide Felodipine Fentanyl Fluconazole Fluoxetine Fluvastatin Fluvoxamine Fosamprenavir                                                                                                                                                                                                                                                                                                                                                                                 | Mestranol Methadone Methimazole Methoxsalen Methylprednisolone Metronidazole Miconazole Midazolam Mifepristone Mirtazapine Mitoxantrone                                                                                                                                                                                                                                                                                                                                    | Pimozide Pravastatin Prednisolone  Primaquine Progesterone Propofol  Propoxyphene Quinidine Quinine Quinupristin Rabeprazole                                                                                                                                                                                                                                                                                                                   | Troleandomycin Valproic acid Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Voriconazole Zafirlukast Ziprasidone   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|
| CYP3A4 Inducers Aminoglutethimide Carbamazepine Fosphenytoin                                                                                                                                                                                                                                                                                                                                                                                                                   | Nafcillin  Nevirapine Oxcarbazepine                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Pentobarbital Phenobarbital  Phenytoin                                                                                                                                                                                                                                                                                                                                                                                                                                     | Primidone Rifabutin Rifampin                                                                                                                                                                                                                                                                                                                                                                                                                   | Rifapentine St. John's wort                                                                                                   |
| CYP3A4 Substrates Albuterol Alfentanil Alprazolam Amlodipine Amprenavir Aprepitant Aripiprazole Atazanavir Atorvastatin Benzphetamine Bisoprolol Bortezomib Bosentan Bromazepam Bromocriptine Buprenorphine Buspirone Busulfan Carbamazapine Cerivastatin Chlordiazepoxide Chloroquine Chlorpheniramine Cisapride Citalopram Clarithromycin Clobazam Clonazepam Clorazepate Cocaine Colchicine Cyclophosphamide Cyclosporine Dantrolene Dapsone Delavirdine Diazepam Digitoxin | Docetaxel Doxepin Doxorubicin Doxycycline Efavirenz Eletriptan Enalapril Eplerenone Ergoloid mesylates Ergonovine Ergotamine Erythromycin Escitalopram Estradiol Estrogens, conj., synthetic Estrogens, conj., equine Estrogens, conj., esterified Estrone Estropipate Ethinyl estradiol Ethosuximide Etoposide Felbamate Felodipine Fentanyl Flurazepam Flutamide Fosamprenavir Fulvestrant Gefitinib Halofantrine Haloperidol Ifosfamide Imatinib Indinavir Irinotecan Isosorbide dinitrate Isosorbide mononitrate | Ketoconazole Lansoprazole Letrozole Levomethadyl acetate hydrochloride Levonorgestrel Lidocaine Losartan Lovastatin Medroxyprogesterone  Mefloquine Mestranol Methadone Methylergonovine Methysergide Miconazole Midazolam Miglustat Mirtazapine Modafinil Montelukast Moricizine Nateglinide Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nimodipine Nisoldipine Nitrendipine Norethindrone Norgestrel Ondansetron Paclitaxel Pergolide Phencyclidine Pimozide | Quetiapine Quinidine Rabeprazole Repaglinide Rifabutin Rifampin Ritonavir Saquinavir Sertraline Sibutramine Sildenafil Simvastatin Sirolimus Sufentanil Tacrolimus Tamoxifen Tamsulosin Telithromycin Teniposide Terbinafine Tetracycline Theophylline Tiagabine Ticlopidine Tolterodine Toremifene Trazodone Triazolam Trimethoprim Trimipramine Troleandomycin Vardenafil Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Zolpidem |                                                                                                                               |  
| Dihydroergotamine Diltiazem Disopyramide   | Isradipine Itraconazole Ketamine   | Pioglitazone Primaquine Progesterone   | Zonisamide Zopiclone   |
|--------------------------------------------|------------------------------------|----------------------------------------|------------------------|  
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH;
LexiComp Inc. 2007: 1899-1912.  
Only major substrates and effective inducers are listed. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference.
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inducers rifampin st john's wort

PgP Inhibitors and PgP/CYP3A Dual Inhibitors: amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, diltiazem, dronedarone, elacridar, erythromycin, felodipine, fexofenadine, fluvoxamine, ginkgo (ginkgo biloba), indinavir, itraconazole, lopinavir, mibefradil, milk thistle (silybum marianum), nelfinavir, nifedipine, nitrendipine, paroxetine, quercetin, quinidine, ranolazine, rifampin, ritonavir, saquinavir, Schisandra chinensis, St John's wort, talinolol, Telaprevir, telmisartan, ticagrelor, tipranavir, tolvaptan, valspodar, verapamil Reference: Internal Clinical Pharmacology Drug-drug interaction (DDI) memo, updated 29-Oct-2012 which summarizes DDI data from three sources including the FDA's "Guidance for Industry, Drug Interaction Studies", the University of Washington's Drug Interaction Database, and Indiana University School of Medicine's Drug Interaction Table. Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible Interactions with Veliparib and Other Drugs and Herbal Supplements The patient ______________________________________ is enrolled on a clinical trial using the experimental study drug **Veliparib**. This clinical trial is sponsored by the National Cancer Institute. This form is addressed to the patient, but includes important information for others who care for this patient. These are the things that you as a prescriber need to know: Veliparib interacts with certain specific enzymes in the liver.  
- The enzymes in question are *CYP1A1, CYP2D6, CYP2C19, and CYP3A4*. Veliparib is metabolized by these enzymes and may be affected by other drugs that inhibit or induce these enzymes.  
To the patient: Take this paper with you to your medical appointments and keep the
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attached information card in your

Veliparib may interact with other drugs which can cause side effects. For this reason, it is very important to tell your study doctors of any medicines you are taking before you enroll onto this clinical trial. It is also very important to tell your doctors if you stop taking any regular medicines, or if you start taking a new medicine while you take part in this study. When you talk about your current medications with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or herbal supplements such as St. John's Wort. It is helpful to bring your medication bottles or an updated medication list with you. Many health care providers can write prescriptions. You must tell all of your health care providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part in a clinical trial.
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these are the things that

Veliparib must be used very carefully with other medicines that need certain **liver enzymes to be** effective or to be **cleared from your system.** Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any medicines and herbal supplements that are considered "strong inducers/inhibitors of *CYP 1A1, CYP2D6,* CYP2C19, and CYP3A4."
- Please be very careful! Over-the-counter drugs (including herbal supplements) may contain ingredients that could interact with your study drug. Speak to your doctors or pharmacist to determine if there could be any side effects.  
- Your regular health care provider should check a frequently updated medical reference or call your study doctor before prescribing any new medicine or discontinuing any medicine. Your study doctor's name is ______________________________________________ and he or she can be contacted at _____________________________________.
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study drug information wallet card

You are enrolled on a clinical trial using the experimental study drug Veliparib. This clinical trial is sponsored by the NCI**. Veliparib may interact with drugs that are**
processed by your liver. Because of this, it is very important to: ➢ Tell your doctors if you stop taking any medicines or if you start taking any new medicines
➢ Tell all of your health care providers (doctors, physician assistants, nurse practitioners, or pharmacists) that you are taking part in a clinical trial
➢ Check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplements such as St. John's Wort
➢ Avoid grapefruit, grapefruit juice, Seville oranges, and starfruit while taking this drug Veliparib interacts with CYP 1A1, 2D6, 2C19, and 3A4, and must be used very carefully with other medicines that interact with these enzymes and proteins.  
- Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any medicines and herbal supplements that are considered "strong inducers/inhibitors of CYP **1A1,**
CYP2D6, CYP2C19, and CYP3A4"
- Before prescribing new medicines, your regular prescribers should go to a frequently-updated medical reference for a list of drugs to avoid, or contact your study doctor.  
- Your study doctor's name is:  
| and can be contacted at:   |
|----------------------------|  
Information for Patients, Their Caregivers, **and Non-Study Healthcare Team on Possible** Interactions with AZD1775 **and Other Drugs and Herbal Supplements** The patient _____________________________________ is enrolled on a clinical trial using the experimental study drug **AZD1775**. This clinical trial is sponsored by the National Cancer Institute. This form is addressed to the patient, but includes important information for others who care for this patient. These are the things that you as a prescriber need to know:  
- The enzyme in question is *CYP 3A4*. AZD1775 is metabolized by CYP3A4 and may be  
  
  
affected by other drugs that inhibit or induce this enzyme. AZD1775 is an inhibitor of CYP 3A4 and may affect the metabolism of other drugs.  
  
To the patient: Take this paper with you to your medical appointments and keep the attached information card in your wallet.
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azd1775 may interact with other

important to tell your study doctors of any medicines you are taking before you enroll onto this clinical trial. It is also very important to tell your doctors if you stop taking any regular medicines, or if you start taking a new medicine while you take part in this study. When you talk about your current medications with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or herbal supplements such as St. John's Wort. It is helpful to bring your medication bottles or an updated medication list with you. Many health care providers can write prescriptions. You must tell all of your health care providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part in a clinical trial. These are the things that you and they need to know:
- Please be very careful! Over-the-counter drugs (including herbal supplements) may contain ingredients that could interact with your study drug. Speak to your doctors or pharmacist to determine if there could be any side effects.  
- Your regular health care provider should check a frequently updated medical reference or call your study doctor before prescribing any new medicine or discontinuing any medicine. Your study doctor's name is ________________________________________________ and he or she can be contacted at_____________________________________  
Study Drug Information Wallet Card  
 important to: ➢ Tell your doctors if you stop taking any medicines or if you start taking any new medicines
➢ Tell all of your health care providers (doctors, physician assistants, nurse practitioners, or pharmacists) that you are taking part in a clinical trial
➢ Check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplements such as St. John's Wort
➢ Avoid grapefruit, grapefruit juice, Seville oranges, and starfruit while taking this drug  
  
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible Interactions with Everolimus and Other Drugs and Herbal Supplements The patient ______________________________________ is enrolled on a clinical trial using the experimental study drug **Everolimus**. This clinical trial is sponsored by the National Cancer Institute. This form is addressed to the patient, but includes important information for others who care for this patient. These are the things that you as a prescriber need to know: Everolimus interacts with certain specific enzymes in the liver.  
- The enzyme in question is *CYP3A4*. Everolimus is metabolized by this enzyme and may be affected by other drugs that inhibit or induce this enzyme.
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to the patient take this

Everolimus may interact with other drugs which can cause side effects. For this reason, it is very important to tell your study doctors of any medicines you are taking before you enroll onto this clinical trial. It is also very important to tell your doctors if you stop taking any regular medicines, or if you start taking a new medicine while you take part in this study. When you talk about your current medications with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or herbal supplements such as St. John's Wort. It is helpful to bring your medication bottles or an updated medication list with you. Many health care providers can write prescriptions. You must tell all of your health care providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part in a clinical trial. These are the things that you and they need to know: Everolimus must be used very carefully with other medicines that need certain liver enzymes to be effective or to be cleared from your system. Before you enroll onto the clinical trial, your study doctor will work with your regular health care providers to review any medicines and herbal supplements that are considered "strong inducers/inhibitors of *CYP3A4*."
- Please be very careful! Over-the-counter drugs (including herbal supplements) may contain ingredients that could interact with your study drug. Speak to your doctors or pharmacist to determine if there could be any side effects.  
- Your regular health care provider should check a frequently updated medical reference or call your study doctor before prescribing any new medicine or discontinuing any medicine. Your study doctor's name is ______________________________________________ and he or she can be contacted at _____________________________________.
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study drug information wallet card

You are enrolled on a clinical trial using the experimental study drug Everolimus. This clinical trial is sponsored by the NCI**. Everolimus may interact with drugs that are**
processed by your liver. Because of this, it is very important to: ➢ Tell your doctors if you stop taking any medicines or if you start taking any new medicines
➢ Tell all of your health care providers (doctors, physician assistants, nurse practitioners, or pharmacists) that you are taking part in a clinical trial
➢ Check with your doctor or pharmacist whenever you need to use an over-the-counter medicine or herbal supplements such as St. John's Wort
➢ Avoid grapefruit, grapefruit juice, Seville oranges, and starfruit while taking this drug  
Everolimus **interacts** with CYP3A4, and must be used  
very carefully with other medicines that interact with these  
enzymes and proteins.  
- Before you enroll onto the clinical trial, your study doctor  
will work with your regular health care providers to review any medicines and herbal supplements that are considered "strong inducers/inhibitors of CYP3A4"  
- Before prescribing new medicines, your regular  
prescribers should go to a frequently-updated medical reference for a list of drugs to avoid, or contact your study doctor.  
- Your study doctor's name is:  
| prescribers should go to a frequently-updated medical  reference for a list of drugs to avoid, or contact your  study doctor.   |
|---------------------------------------------------------------------------------------------------------------------------------|
| - Your study doctor's name is:  and can be contacted at:                                                                        |
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appendix c medications that may

The following table presents a list of drugs that prolong, may prolong, or are unlikely to prolong the QTc. Please note that this list is frequently updated. For the most current list of medications, users should be directed to the following website: *http://crediblemeds.org/*  
| Drugs that are generally  accepted to have a risk of  causing Torsades de Pointes   | Drugs that in some reports have been  associatedwith Torsades de Pointes  and/or QTc prolongation but at this  time lack substantial evidence for  causing Torsades de Pointes   | Drugs that, in some reports, have been  weakly associated with Torsades de  Pointes and/or QTc prolongation but that  are unlikely to be a risk for Torsades de  Pointes when used in usual recommended  dosages and in subjects without other risk  factors (e.g., concomitant QTc prolonging  drugs, bradycardia, electrolyte  disturbances, congenital long QTc  syndrome, concomitant drugs that inhibit  metabolism)   |
|-------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Generic/Brand Name                                                                  | Generic/Brand Name                                                                                                                                                               | Generic/Brand Name                                                                                                                                                                                                                                                                                                                                                                                                          |
| Amiodarone /Cordarone®                                                              | Alfuzosin /Uroxatral®                                                                                                                                                            | Amitriptyline /Elavil®                                                                                                                                                                                                                                                                                                                                                                                                      |
| Amiodarone /Pacerone®                                                               | Amantadine /Symmetrel®                                                                                                                                                           | Ciprofloxacin /Cipro®                                                                                                                                                                                                                                                                                                                                                                                                       |
| Arsenic trioxide /Trisenox®                                                         | Atazanavir /Reyataz®                                                                                                                                                             | Citalopram /Celexa®                                                                                                                                                                                                                                                                                                                                                                                                         |
| Astemizole /Hismanal®                                                               | Azithromycin /Zithromax®                                                                                                                                                         | Clomipramine /Anafranil®                                                                                                                                                                                                                                                                                                                                                                                                    |
| Bepridil /Vascor®                                                                   | Chloral hydrate /Noctec®                                                                                                                                                         | Desipramine /Pertofrane®                                                                                                                                                                                                                                                                                                                                                                                                    |
| Chloroquine /Aralen®                                                                | Clozapine /Clozaril®                                                                                                                                                             | Diphenhydramine /Benadryl®                                                                                                                                                                                                                                                                                                                                                                                                  |
| Chlorpromazine /Thorazine®                                                          | Dolasetron /Anzemet®                                                                                                                                                             | Diphenhydramine /Nytol®                                                                                                                                                                                                                                                                                                                                                                                                     |
| Cisapride /Propulsid®                                                               | Dronedarone /Multaq®                                                                                                                                                             | Doxepin /Sinequan®                                                                                                                                                                                                                                                                                                                                                                                                          |
| Clarithromycin /Biaxin®                                                             | Felbamate /Felbatrol®                                                                                                                                                            | Fluconazole /Diflucan®                                                                                                                                                                                                                                                                                                                                                                                                      |
| Disopyramide /Norpace®                                                              | Flecainide /Tambocor®                                                                                                                                                            | Fluoxetine /Sarafem®                                                                                                                                                                                                                                                                                                                                                                                                        |
| Dofetilide /Tikosyn®                                                                | Foscarnet /Foscavir®                                                                                                                                                             | Fluoxetine /Prozac®                                                                                                                                                                                                                                                                                                                                                                                                         |
| Domperidone /Motilium®                                                              | Fosphenytoin /Cerebyx®                                                                                                                                                           | Galantamine /Reminyl®                                                                                                                                                                                                                                                                                                                                                                                                       |
| Droperidol /Inapsine®                                                               | Gatifloxacin /Tequin®                                                                                                                                                            | Imipramine /Norfranil®                                                                                                                                                                                                                                                                                                                                                                                                      |
| Erythromycin /Erythrocin®                                                           | Gemifloxacin /Factive®                                                                                                                                                           | Itraconazole /Sporanox®                                                                                                                                                                                                                                                                                                                                                                                                     |
| Erythromycin /E.E.S.®                                                               | Granisetron /Kytril®                                                                                                                                                             | Ketoconazole /Nizoral®                                                                                                                                                                                                                                                                                                                                                                                                      |
| Halofantrine /Halfan®                                                               | Indapamide /Lozol®                                                                                                                                                               | Mexiletine /Mexitil®                                                                                                                                                                                                                                                                                                                                                                                                        |
| Haloperidol /Haldol®                                                                | Isradipine /Dynacirc®                                                                                                                                                            | Nortriptyline /Pamelor®                                                                                                                                                                                                                                                                                                                                                                                                     |
| Ibutilide /Corvert®                                                                 | Lapatinib /Tykerb®                                                                                                                                                               | Paroxetine /Paxil®                                                                                                                                                                                                                                                                                                                                                                                                          |
| Levomethadyl /Orlaam®                                                               | Lapatinib /Tyverb®                                                                                                                                                               | Protriptyline /Vivactil®                                                                                                                                                                                                                                                                                                                                                                                                    |
| Mesoridazine /Serentil®                                                             | Levofloxacin /Levaquin®                                                                                                                                                          | Sertraline /Zoloft®                                                                                                                                                                                                                                                                                                                                                                                                         |  
| Drugs that are generally  accepted to have a risk of  causing Torsades de Pointes   | Drugs that, in some reports, have been  weakly associated with Torsades de  Pointes and/or QTc prolongation but that  are unlikely to be a risk for Torsades de  Pointes when used in usual recommended  dosages and in subjects without other risk  factors (e.g., concomitant QTc prolonging  drugs, bradycardia, electrolyte  disturbances, congenital long QTc  syndrome, concomitant drugs that inhibit  metabolism)   |                              |
|-------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|
| Generic/Brand Name                                                                  | Generic/Brand Name                                                                                                                                                                                                                                                                                                                                                                                                          | Generic/Brand Name           |
| Methadone /Dolophine®                                                               | Lithium /Lithobid®                                                                                                                                                                                                                                                                                                                                                                                                          | Solifenacin /VESIcare®       |
| Methadone /Methadose®                                                               | Lithium /Eskalith®                                                                                                                                                                                                                                                                                                                                                                                                          | Trimethoprim-Sulfa /Sulfa®   |
| Pentamidine /Pentam®                                                                | Moexipril/HCTZ /Uniretic®                                                                                                                                                                                                                                                                                                                                                                                                   | Trimethoprim-Sulfa /Bactrim® |
| Pentamidine /NebuPent®                                                              | Moxifloxacin /Avelox®                                                                                                                                                                                                                                                                                                                                                                                                       | Trimipramine /Surmontil®     |
| Pimozide /Orap®                                                                     | Nicardipine /Cardene®                                                                                                                                                                                                                                                                                                                                                                                                       |                              |
| Probucol /Lorelco®                                                                  | Nilotinib /Tasigna®                                                                                                                                                                                                                                                                                                                                                                                                         |                              |
| Procainamide /Pronestyl®                                                            | Octreotide /Sandostatin®                                                                                                                                                                                                                                                                                                                                                                                                    |                              |
| Procainamide /Procan®                                                               | Ofloxacin /Floxin®                                                                                                                                                                                                                                                                                                                                                                                                          |                              |
| Quinidine /Cardioquin®                                                              | Ondansetron /Zofran®                                                                                                                                                                                                                                                                                                                                                                                                        |                              |
| Quinidine /Quinaglute®                                                              | Oxytocin /Pitocin®                                                                                                                                                                                                                                                                                                                                                                                                          |                              |
| Sotalol /Betapace®                                                                  | Paliperidone /Invega® Drugs that in some reports have been  associatedwith Torsades de Pointes  and/or QTc prolongation but at this  time lack substantial evidence for  causing Torsades de Pointes Perflutren lipid microspheres                                                                                                                                                                                          |                              |
| Sparfloxacin /Zagam®                                                                | /Definity®                                                                                                                                                                                                                                                                                                                                                                                                                  |                              |
| Terfenadine /Seldane®                                                               | Quetiapine /Seroquel®                                                                                                                                                                                                                                                                                                                                                                                                       |                              |
| Thioridazine /Mellaril®                                                             | Ranolazine /Ranexa® Risperidone /Risperdal® Roxithromycin* /Rulide® Sertindole /Serlect® Sertindole /Serdolect® Sunitinib /Sutent® Tacrolimus /Prograf® Tamoxifen /Nolvadex® Telithromycin /Ketek® Tizanidine /Zanaflex® Vardenafil /Levitra® Venlafaxine /Effexor® Voriconazole /VFend® Ziprasidone /Geodon®                                                                                                               |                              |
| References:                                                                         |                                                                                                                                                                                                                                                                                                                                                                                                                             |                              |
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appendix d patient study diaries

Study Name: Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors
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ctep study id 9149 patient

Instructions to the patient: Please complete this form and return to the research nurse or doctor every cycle (28 days) You will take: Veliparib and Temozolomide Medication dose: Take Veliparib capsules twice each day (morning and evening) on days 1 to 7 and take temozolomide capsules once each day on days 1 to 5 Take temozolomide capsules one at a time with a full glass of water. Temozolomide capsules should not be opened, crushed, or chewed. Temozolomide capsules should be swallowed whole and never chewed. If you vomit the capsules, do not take a second dose. Capsules can be taken with or without food, but please try and take them at the same time every day, and if possible, always with or always without food. Avoid grapefruit, grapefruit juice, Seville oranges, starfruit, and the herbal supplement St. John's Wort while taking this drug. Do not open, crush, or chew Veliparib capsules.  
Cycle number: _________ Start date: _________ Patient Signature: _____________________________________  
| Time taken   | Time taken          | COMMENTS:                |    |
|--------------|---------------------|--------------------------|----|
| Veliparib    | Temozolomide        | Side effects/missed dose |    |
| DATE         | DAY                 | AM                       | PM |
| 1 2 3 4 5 6  | No drug taken today |                          |    |
| 7            | No drug taken today |                          |    |
| 8            | No drug taken today | No drug taken today      |    |
| 9            | No drug taken today | No drug taken today      |    |
| 10           | No drug taken today | No drug taken today      |    |
| 11           | No drug taken today | No drug taken today      |    |
| 12           | No drug taken today | No drug taken today      |    |
| 13           | No drug taken today | No drug taken today      |    |
| 14           | No drug taken today | No drug taken today      |    |
| 15           | No drug taken today | No drug taken today119   |    |  
| 16   | No drug taken today   | No drug taken today   |
|------|-----------------------|-----------------------|
| 17   | No drug taken today   | No drug taken today   |
| 18   | No drug taken today   | No drug taken today   |
| 19   | No drug taken today   | No drug taken today   |
| 20   | No drug taken today   | No drug taken today   |
| 21   | No drug taken today   | No drug taken today   |
| 22   | No drug taken today   | No drug taken today   |
| 23   | No drug taken today   | No drug taken today   |
| 24   | No drug taken today   | No drug taken today   |
| 25   | No drug taken today   | No drug taken today   |
| 26   | No drug taken today   | No drug taken today   |
| 27   | No drug taken today   | No drug taken today   |
| 28   | No drug taken today   | No drug taken today   |
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patient study diary

Study Name: Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors
untitled h1
ctep study id 9149

Patient Name: ______________________________________________________ Instructions to the patient: Please complete this form and return to the research nurse or doctor every cycle (21 days) You will take: AZD1775 and carboplatin Medication dose: Take AZD1775 capsules twice each day on days 1 and 2 (morning and evening) and once on day 3 (either in the morning or evening) at least two hours before or two hours after a meal. Do not open, crush, or chew the capsules. Avoid grapefruit, grapefruit juice, Seville oranges, starfruit, and the herbal supplement St. John's Wort while taking this drug.  
Carboplatin will be given by intravenous administration at the day hospital on day 1 **only** of each 21-day cycle.  
Cycle number: _________ Start date: _________ Patient Signature: _____________________________________  
| DATE                                                                                                                     | DAY                                                                                                                                            | Time taken   | COMMENTS:   |
|--------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|--------------|-------------|
| AZD1775                                                                                                                  | Side effects/missed dose                                                                                                                       |              |             |
| AZD1775 and carboplatin  will be given in clinic today.  Take one dose of AZD1775  in the evening Time evening: ________ |                                                                                                                                                |              |             |
| 1                                                                                                                        | Take 2 doses of AZD1775  today. Take one dose of  AZD1775in the morning  and one in the evening. Time morning: ________ Time evening: ________ |              |             |
| 2                                                                                                                        | Take only one dose of  AZD1775 today Time: _________                                                                                           |              |             |
| 3 4                                                                                                                      | No drug taken today                                                                                                                            |              |             |
| 5                                                                                                                        | No drug taken today                                                                                                                            |              |             |
| 6                                                                                                                        | No drug taken today                                                                                                                            |              |             |
| 7                                                                                                                        | No drug taken today                                                                                                                            |              |             |
| 8                                                                                                                        | No drug taken today                                                                                                                            |              |             |
| 9                                                                                                                        | No drug taken today                                                                                                                            |              |             |
| 10                                                                                                                       | No drug taken today                                                                                                                            |              |             |  
| DATE    | DAY                      | Time taken   | COMMENTS:   |
|---------|--------------------------|--------------|-------------|
| AZD1775 | Side effects/missed dose |              |             |
| 11      | No drug taken today      |              |             |
| 12      | No drug taken today      |              |             |
| 13      | No drug taken today      |              |             |
| 14      | No drug taken today      |              |             |
| 15      | No drug taken today      |              |             |
| 16      | No drug taken today      |              |             |
| 17      | No drug taken today      |              |             |
| 18      | No drug taken today      |              |             |
| 19      | No drug taken today      |              |             |
| 20      | No drug taken today      |              |             |
| 21      | No drug taken today      |              |             |
patient study diary
ctep study id 9149

Study Name: Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors
patient study diary
ctep study id 9149 patient

Instructions to the patient: Please complete this form and return to the research nurse or doctor every cycle (28 days) You will take: Everolimus Medication dose: Take everolimus tablets once a day every day for 28 days. Tablets should not be crushed or chewed, and should be swallowed whole with a glass of water. Tablets can be taken with or without food, but please try and take them at the same time every day, and if possible, always with or always without food. If you vomit the tablet, do not take another tablet that day. Avoid grapefruit, grapefruit juice, Seville oranges, starfruit, and the herbal supplement St. John's Wort while taking this drug. Caregivers should wash their hands with soap and water after touching the tablets.  
Cycle number: _________ Start date: _________ Patient Signature: _____________________________________  
| DATE                             | DAY                      | Time taken   | COMMENTS:   |
|----------------------------------|--------------------------|--------------|-------------|
| Everolimus                       | Side effects/missed dose |              |             |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 |                          |              |             |  
| DATE                                      | DAY                      | Time taken   | COMMENTS:   |
|-------------------------------------------|--------------------------|--------------|-------------|
| Everolimus                                | Side effects/missed dose |              |             |
| 15 16 17 18 19 20 21 22 23 24 25 26 27 28 |                          |              |             |
patient study diary
ctep study id 9149 patient

Study Name: Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors
patient study diary
ctep study id 9149 patient

Instructions to the patient: Please complete the form on the next page and return it to the research nurse or doctor every cycle (28 days). Store trametinib DMSO tablets in the refrigerator. Keep the tablets in the bottle they come in and do not move to a pill holder. Do not take out the anti-moisture cube or packet. You will take: Trametinib DMSO Medication dose: Take Trametinib DMSO tablets once a day for 28 days with a full glass of water either 1 hour before or 2 hours after a meal. If you vomit the tablets, do not take an additional dose. If you miss a dose, take it as soon as you remember. If it is less than 12 hours until your next dose, skip the dose.  
Cycle number: _________ Start date: _________ Patient Signature: _____________________________________  
| DATE                             | DAY                      | Time taken   | COMMENTS:   |
|----------------------------------|--------------------------|--------------|-------------|
| Trametinib DMSO                  | Side effects/missed dose |              |             |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 |                          |              |             | | DATE                                      | DAY                      | Time taken   | COMMENTS:   |
|-------------------------------------------|--------------------------|--------------|-------------|
| Trametinib DMSO                           | Side effects/missed dose |              |             |
| 15 16 17 18 19 20 21 22 23 24 25 26 27 28 |                          |              |             |
patient study diary
study chart

Treatment cycles will be repeated as long as you are tolerating the study drug and your cancer is either stable or getting better. Each cycle is numbered in consecutive order. The chart below shows what will happen during Cycle 1 and future cycles. The left-hand column shows the day in the cycle, and the right-hand column tells you what will happen on that day. This schedule shows what will happen to you after you sign the consent and start the study.  
| Day                            | What to do and what will happen to you                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                |
|--------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|
| Before  starting  study  drugs | - Check in at the Outpatient Clinic - Get routine blood tests - EKG  - Eye exam (depending on the study treatment) - Pregnancy test - Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider - CT scan will be done                                                                                                                                                                                                                                                       |                                                                                |
| Day 1                          | - Check in at the Outpatient Clinic - Based on analysis of gene variations in your tumor, you may be given one of  the following drugs: Trametinib DMSO, or everolimus, or Veliparib and  temozolomide, or AZD1775 and carboplatin - Have a history taken of how you feel and undergo a physical examination by a  Health Care Provider - Get routine blood tests - During the first week, have a tumor biopsy to confirm your genetic testing  report (no biopsy if you already had one for screening on this study) |                                                                                |
| Day 8                          | - Continue taking your study drug by mouth each day (if taking everolimus or  Trametinib DMSO) according to the instructions in your study medication  diary - Get routine blood tests (Cycle 1 only)                                                                                                                                                                                                                                                                                                                 |                                                                                |
| Cycle 2                        | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | For patients getting AZD1775 plus carboplatin only, check in at the Outpatient |
| Day 1                          | Clinic (first day of every cycle only).                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                |
| -                              | Continue taking your study drug by mouth each day                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                |
| -                              | Eye exam (depending on the study treatment)                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                |
| Cycle 3                        | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | CT scans to determine how your tumor is responding to the treatment will be    |
| onwards                        | done every 2 cycles (less often if you have been on study for more than one  year.                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                |
| -                              | Echocardiogram (depending on the study treatment) to check for possible  damage to your heart may be done every 3 cycles                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                |  
On the days that you will be taking the study drug you will be asked to fill in a diary to show when you took the study drug and how many tablets or capsules you took, and report any side effects that you may have had.
appendix e mpact (9149) sample
study chart

This protocol collects formalin-fixed tumor samples (2 cores) from the initial screening biopsy procedure. Please consult with the study PI for more information and discuss the handling requirements for each core sample collected with the interventional radiologist. Sample collection and shipping items to be purchased by each participating site:
Biopsy collection*:
- Pre-filled 10% neutral-buffered formalin specimen jar, 30 mL (e.g., Leica 3800770), one jar per core sample Blood collection:
- 2 cell-free DNA BCT tubes, 10 mL (e.g., Streck 218961)
Shipping supplies:
- Specimen bags (zip-lock) - Absorbent paper for packing - Controlled room temperature (CRT) gel packs (e.g., STT-521-500 Saf-T-Temp CRT PCM Paks)
- Small thermo-shipper boxes (e.g., Thermo-safe 14100-434)
appendix e mpact (9149) sample
notes

Follow manufacturer's instructions for specimen collection and handling. Put shipping manifest in a plastic zip-lock bag in case of sample leakage. Include the Clinical Center number,study number (9149), patient ID, site of biopsy, patient diagnosis, biopsy/blood collection date, and fixation time (i.e., initial/date/time placed into 10% NBF) on the manifest. Do not include patient identifiers.  
Please do not collect samples on Fridays for overnight delivery as FNLCR cannot accept weekend courier delivery. If Friday collection is unavoidable, ship the samples via overnight delivery but contact **NCI-FrederickMPACTCLIA@mail.nih.gov** and include two CRT gel packs in the shipper boxes. The samples will be stable until Monday delivery.  
*Archival FFPE tumor blocks may be acceptable if collected within 6 months of registration and if the patient has not receive d targeted or investigational therapy since collection; check with study investigator for details  
| GENETIC SAMPLE SHIPPING MANIFEST   |                                                         |                                                                        |            |                                      |
|------------------------------------|---------------------------------------------------------|------------------------------------------------------------------------|------------|--------------------------------------|
| Protocol 9149                      | Shipping date:                                          | Carrier:                                                               |            |                                      |
| SHIP FROM: Ordering  Physician/PI: | SHIP TO:                                                | MoCha Histology Laboratory (K. Benauer)                                |            |                                      |
| Address:                           | Address:                                                | Leidos Biomedical Research Inc. (FNLCR)                                |            |                                      |
|                                    | 1050 Boyles St. Bldg 321, Room #107 Frederick, MD 21702 |                                                                        |            |                                      |
| Contact Name:  Telephone:          | Telephone:                                              | 301-846-6083/301-846-1535                                              |            |                                      |
| Email:                             | Email:                                                  | NCI-FrederickMPACTCLIA@mail.nih.gov No. Containers/Tubes Fixation Time |            |                                      |
| Item                               | Unique GeneMed ID* (Sample ID)                          | Biopsy Site                                                            | Diagnosis  | Date                                 |
| Collected                          | Biopsy                                                  | Blood                                                                  | FFPE block | Into 10%NBF-Site (Initial/Date/Time) |
| 1 2 3 4 5 6 7 8                    | TOTAL No. ITEMS                                         |                                                                        |            |                                      |
| COMMENTS:                          |                                                         |                                                                        |            |                                      |  
COMMENTS:  
*DO NOT include patient identifiers  
APPENDIX F: Biopsy Sequencing Results and Analysis Form Form begins on the next page.
appendix e mpact (9149) sample
ctep-9149 tumor specimen report

Patient ID:
Report Date:  
| Patient ID:             | MoCha ID:      | HIS          |               |
|-------------------------|----------------|----------|---------------|
| Principal Investigator: | Alice Chen, MD |          |               |
| Diagnosis: Biopsy Site: | Date           | DNA/cDNA | Tumor Content |
| Collected:              | Block Source:  | (%)1 :   |               |  
  
This report identifies only actionable MOIs (aMOIs) relevant to the genes currently validated for clinical application.  
aMOIs not detected are not otherwise identified.  
134  
Molecular Characterization Laboratory  
Frederick National Laboratory for Cancer Research  
(Leidos Biomedical Research, Inc.)  
459 Miller Drive, Frederick, MD 21702  
301.846.7689  
CLIA Laboratory ID 21D2097127  
| DNA Repair : None identified (delete this text if variants are reported) aMOIs Detected Gene Chr. Position REF (hg19) ALT (Tumor) Transcript   | Amino Acid  Change   | VAF   | Variant ID   |
|------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|-------|--------------|
| ID                                                                                                                                             |                      |       |              |
| 1Preanalytical preparation was performed by the MoCha Histology Laboratory, 321 Ware Drive, Frederick, MD 21702 [CLIA ID 21D2137521]. Reported |                      |       |              |  
```
1Preanalytical preparation was performed by the MoCha Histology Laboratory, 321 Ware Drive, Frederick, MD 21702 [CLIA ID 21D2137521]. Reported
assay characteristics cannot be guaranteed for specimens that present a tumor content below 20%.
KEY: NA=Not Applicable; Chr=Chromosome; REF (HG19)=Reference base, Human Reference Genome hg19); ALT (Tumor)=Variant base
Comments:

SIGNATURE APPROVAL:
The signature below attests that the signee has reviewed the data and results reported and concurs with the stated conclusions.

```  
DISCLAIMER: *This assay is considered a Laboratory Developed Test (LDT). Its performance characteristics have been determined through extensive* testing although it has not been cleared by the US Food and Drug Administration and such approval is not required for clinical implementation. Furthermore, any Comments included in this report are strictly interpretive and the opinion of the reviewer. This laboratory is certified under the Clinical Laboratory Improvement Amendments (CLIA) for the performance of high-complexity molecular testing for clinical purposes.  
Methodology, Scope, and Application: The sequencing test utilizes the Thermo Fisher Scientific Oncomine® Comprehensive Assay v3.0 (OCAv3), a nextgeneration sequencing (NGS) assay that utilizes a multiplex polymerase chain reaction (PCR) with *DNA extracted from formalin-fixed tissue for sequencing*  
  
on the Ion S5 XL platform. The OCv3 NGS Assay can reliably identify the presence or absence of known (reported in COSMIC or ClinVar databases) aMOIs in 15 DNA repair genes, with results compared to Human Reference Genome hg19. The table below lists these genes with the aMOIs t *hat can be identified. The* remainder of the genes included in the Oncomine panel include no relevant hotspots. Novel deleterious calls and truncating mutations (frameshift indels and/or nonsense mutations) will also be considered actionable. The OCAV3 NGS Assay is a laboratory developed test designed to find gene mutations within tumors (somatic mutations). It was not designed to find hereditary mutations. Analytical Sensitivity and Specificity: The OCAV3 NGS Assay has been determined to be suitably analytically sensitive and specific for the various types of abnormalities within its reportable range, demonstrating 97.18% sensitivity compared with orthogonal assay results and 100% s *pecificity for the mutation types* reported. 99.99% or greater reproducibility has been demonstrated. All quality measures for this assay were within defined assay parameters.  
135  
Molecular Characterization Laboratory  
Frederick National Laboratory for Cancer Research  
(Leidos Biomedical Research, Inc.)  
459 Miller Drive, Frederick, MD 21702  
301.846.7689  
CLIA Laboratory ID 21D2097127  
| Gene                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Pathway    | Identifiable aMOIs (defined as Coding Sequence Change)                                                                        | Functionality   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|-------------------------------------------------------------------------------------------------------------------------------|-----------------|
| c.1009C>T, c.1009C>A, c.1010G>C, c.1010G>A, c.5558A>T, c.6490G>C, c.6490G>A, c.7325A>C,  c.7325A>G, c.7327C>G, c.7328G>A, c.8083G>T, c.8083G>A, c.8084G>C, c.8494C>T, c.8494C>A,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |            |                                                                                                                               |                 |
| ATM                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | DNA repair | Loss                                                                                                                          |                 |
| c.8624A>G, c.8624A>C, c.8625T>A, c.8668C>G, c.8669T>G, c.8860T>A, c.8861A>G, c.9022C>A, c.9022C>T, c.9023G>T, c.9023G>A                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |            |                                                                                                                               |                 |
| NBN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| RAD51                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| RAD51B                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| RAD51C                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| RAD51D                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| PALB2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| c.5363G>T, c.5277+1G>A, c.441+2T>G, c.5468-40T>A, c.5467G>A, c.5359T>A, c.5332+1G>A,  c.5331_5332+1delinsCAACAT, c.5324T>G, c.5324T>A, c.5297T>G, c.5291T>C, c.5278-2del, c.5212G>A,  c.5194-12G>A, c.5153-1G>C, c.5152+3A>C, c.5152+1G>T, c.5143A>C, c.5123C>A, c.5117G>A, c.5095C>T, c.5074+1G>A, c.5074G>A, c.5074G>C, c.5074G>T, c.5054C>T, c.5053A>G,  c.4987-1G>A, c.4986+6T>C, c.4986+6T>G, c.4986+4A>G, c.4986+4A>C, c.4986+4A>T, c.4675+3A>T,  c.4675+1G>A, c.4675G>A, c.4675G>C, c.4484G>T, c.4357+1G>A, c.4185G>A, c.4097-1G>A,  c.547+2T>A, c.302-1G>C, c.302-3C>G, c.213-3C>G, c.213-11T>G, c.213-12A>G, c.212+3A>G,  c.212G>A, c.211A>G, c.191G>A, c.181T>G, c.131G>A, c.130T>A, c.122A>G, c.115T>C, c.110C>A, c.65T>C, c.3G>T, c.2T>C, c.2T>G, c.1A>G, c.5513T>A |            |                                                                                                                               |                 |
| BRCA1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | DNA repair | Loss                                                                                                                          |                 |
| c.2T>G, c.3G>T, c.475G>A, c.475+1G>A, c.476-2A>G, c.631G>C, c.631G>A, c.682-2A>G, c.7007G>C  c.7007G>T, c.7008-2A>T, c.7617+1G>A, c.7618-1G>A, c.7878G>C, c.7879A>T, c.7976G>C, c.7988A>T,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |            |                                                                                                                               |                 |
| BRCA2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | DNA repair | Loss                                                                                                                          |                 |
| c.8009C>T, c.8165C>G, c.8167G>C, c.8168A>G, c.8243G>A, c.8487+1G>A, c.8953+1G>T,  c.8954- 3C>G, c.9154C>T                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |            |                                                                                                                               |                 |
| CHEK1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| CHEK2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | DNA repair | c.1556G>A, c.1169A>G, c.1141A>G                                                                                               | Loss            |
| FANCA                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| MRE11A                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | DNA repair | Novel loss of function frameshift or nonsense mutation                                                                        | Loss            |
| IDH1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | DNA repair | c.394C>A, c.395_396GT>AC, c.394_395CG>GT, c.394_395CG>TC, c.395G>A, c.395G>T, c.394C>G,  c.394C>T                             | Altered         |
| IDH2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | DNA repair | c.515_516GG>AT, c.516G>C, c.516G>T, c.515G>A, c.515G>C, c.515G>T, c.514A>T,  c.514A>G, c.419G>A, c.419G>T, c.418C>G, c.418C>T | Altered         |
| aMOI COSMIC ID may be found at: Catalog of Somatic Mutations in Cancer, https://cancer.sanger.ac.uk/cosmic                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |            |                                                                                                                               |                 |
appendix e mpact (9149) sample
appendix g molecular tumor board

The Molecular Tumor Board is a multidisciplinary group with expertise in molecular and clinical genetics, gene analysis, pharmacogenomics, pharmacodynamics, statistics, and bioinformatics assembled to review and select the genetic variants being assessed on this study. The Board will meet on an ad hoc basis to review and discuss findings and results but will not influence initial treatment assignments.  
| Name                  | Affiliation           | Specialty                               |
|-----------------------|-----------------------|-----------------------------------------|
| Alice Chen, MD        | CTEP/DCTD/NCI         | Clinical oncology                       |
| James H. Doroshow, MD | DCTD/NCI              | Molecular and clinical oncology         |
| Jeff Hildesheim, PhD  | CCBB/NCI              | Molecular oncology                      |
| Robert Kinders, PhD   | Leidos Biomed., FNLCR | Molecular oncology and pharmacodynamics |
| Chris Karlovich, PhD  | Leidos Biomed., FNLCR | Molecular oncology and genetic analysis |
| Paul Meltzer, MD, PhD | GB/CCR/NCI            | Molecular oncology and genetic analysis |
| Eric Polley, PhD      | Mayo                  | Statistics                              |
| Yves Pommier, MD, PhD | LMP/CCR/NCI           | Molecular oncology                      |
| Larry Rubinstein, PhD | DCTD/NCI              | Statistics                              |
| Jim Tricoli, PhD      | Leidos Biomed., FNLCR | Molecular oncology and genetic analysis |
| Mickey Williams, PhD  | Leidos Biomed., FNLCR | Molecular oncology and genetic analysis |  
| —Variant Annotation Table -   | Patient ID:  9149101aa01        Sample ID:  9149-MOCK-as01   |             |            |           |        |               |              |       |    |    |    |      |              |       |
|-------------------------------|--------------------------------------------------------------|-------------|------------|-----------|--------|---------------|--------------|-------|----|----|----|------|--------------|-------|
| Sift                          | Sift                                                         | COSMIC      | REF        | ALT       | Allele | Read          | Codon        | A     |    |    |    |      |              |       |
| aMOI                          | Drug                                                         | HP          | Impact     | d DSNP id | HGMD   | Chr           | Position     |       |    |    |    |      |              |       |
| Predict                       | Score                                                        | (hg19)      | (tumor)    | Freq      | Depth  | Change        | Change       |       |    |    |    |      |              |       |
| PTEN    Loss                  | Everolimus                                                   | STOP_GAINED | 10         | 89717672  | T      | 0.60          | 1250 Coa/Tga | R233* |    |    |    |      |              |       |
| Yes                           | P13K                                                         | u           |            |           |        |               |              |       |    |    |    |      |              |       |
| Yes                           | BRAE     Gain                                                | RAS         | GSK1120212 | DAMAGING  | 0.01   | nonsynonymous | i            | 426   | 7  | A  | T  | 0.68 | 1483 gTg/gAg | V600E |
|                               |                                                              |             |            |           |        |               |              |       |    |    |    |      |              |       |
appendix h example tumor variant
- legend -

| –Patient Clinical Information Report -                                                                          |                                                                                             |                                   |                  |
|-----------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|-----------------------------------|------------------|
| Field Name                                                                                                      | Description                                                                                 | Patient ID                        | 91491018801      |
| aMOI                                                                                                            | Yes/No: Is the variant one of the actionable mutations for the MPACT trial?                 | Gender                            | M                |
| Gene                                                                                                            | Gene symbol for location of variant. Links to COSMIC website on that gene                   | Histologic Dx                     | Melanoma         |
| Type                                                                                                            | Type: Is this gene Gain of function or Loss of function?                                    | Date of Diagnosis                 | 02/12/2013       |
| Sift Predict                                                                                                    | Damaging/Tolerated: SIFT prediction for non-synonymous variants                             | Age at Diagnosis                  | 5                |
| The score is the normalized probability that the amino acid change is tolerated. The amino acid substitution is |                                                                                             |                                   |                  |
| Sift Score                                                                                                      | predicted damaging is the score is <= 0.05, and tolerated if the score is > 0.05.           | –Sequencing Data Summary Report - |                  |
| HP                                                                                                              | Is the variant in a homopolymer region? If so, display the length of the homopolymer region |                                   |                  |
| Impact                                                                                                          | Functional impact of variant                                                                | Sample ID                         | 9149-MOCK-aa01   |
| dbSNPid                                                                                                         | If available, dbSNP ID                                                                      | Date of Sequencing Data Uploaded  | 01/09/2014 15:28 |
| HGMD                                                                                                            | Is the variant in the HGMD database? If so, link goes to HGMD website                       | completed                         |                  |
| Lab Review of Variant Report                                                                                    |                                                                                             |                                   |                  |
| COSMICid                                                                                                        | Is the variant in COSMIC, if so, link to the variant in COSMIC                              | (01/10/2014 08:28)                |                  |
| Date of Mutation Summary Report                                                                                 | 01/10/2014 10:28                                                                            |                                   |                  |
| Pathway                                                                                                         | RAS, PI3K, or DNA repair                                                                    | Actionable Mutation               |                  |
| Chr                                                                                                             | Chromosome                                                                                  | yes                               |                  |
| Position                                                                                                        | Position of variant in chromosome based on hg19                                             |                                   |                  |
| REF                                                                                                             | Reference base (VCF format, from hg19)                                                      |                                   |                  |
| ALT                                                                                                             | Variant base (VCF format)                                                                   |                                   |                  |
| Allele Frequency                                                                                                | Variant allele frequency estimate based on present of reads supporting the variant          |                                   |                  |
| Read Depth                                                                                                      | Total number of reads at the position                                                       |                                   |                  |
| Codon change                                                                                                    | Codon change from reference                                                                 |                                   |                  |
| AA change                                                                                                       | Amino Acid change from reference                                                            |                                   |                  |
appendix h example tumor variant
-patient clinical information report -

Veliparib is an orally available, small molecule inhibitor of PARP. Preclinical and clinical data show that inhibition of PARP potentiates the effects of DNA-damaging chemotherapeutic drugs such as the alkylating agent temozolomide [67]. In this study, Veliparib and temozolomide will be administered to patients with defects in DNA repair pathways.
appendix h example tumor variant
nonclinical studies

One of the most studied alkylating agents in combination with PARP inhibition is temozolomide, which is used in the treatment of CNS tumors and melanoma. In vitro, potentiation of temozolomide-induced cytotoxicity was observed in the MMR-deficient HCT-116 cell line. In nonclinical models of murine melanoma, dose-dependent potentiation of temozolomide was demonstrated with 12.5 mg/kg BID of orally administered Veliparib that was identified as the maximally efficacious dose (AUC, 3 µg•hr/mL) [100]. Preliminary human pharmacokinetic (PK) results indicate that an oral dose of 40 mg Veliparib BID achieves the exposure (AUC) that was maximally effective in murine efficacy models. The predicted efficacious exposures are below Veliparib concentrations that resulted in a NOAEL in repeated-dose toxicity studies in rats and dogs. The PK profile of Veliparib was evaluated in tumor-bearing rats by measuring drug in plasma as well as in brain and tumor tissues. After multiple doses of Veliparib (50 mg/kg/day), the concentration of the compound 2 hours after dosing (near Cmax) was 1.36 ± 0.16 μg/mL in plasma, 0.72 ± 0.12 μg/g in brain, and 3.00 ± 0.16 μg/g in tumor tissue. Co-administration with temozolomide did not alter the plasma pharmacokinetic profile of Veliparib.  
 In a separate study in rats in which Veliparib was combined with temozolomide, observed toxicities were consistent with exacerbation of known temozolomide toxicity. Co-administration of temozolomide at 16 mg/kg/day and Veliparib at doses of 12.5 and 25 mg/kg/day (divided BID) resulted in increased toxicity over that observed with temozolomide administration alone, effecting bone marrow, lymphoid tissues, testes, and ovaries. Most toxicological findings   
  
  
  
skeletal ossification. The rat is the most sensitive species for fetal toxicity, with the Cmax at the NOEL for rat and rabbit of 0.02 and 2.4 µg/mL, respectively. There are no data regarding the effects of Veliparib on pregnancy in humans.
appendix h example tumor variant
clinical studies

Pharmacokinetic results from a Phase I study of Veliparib in combination with temozolomide (Study M06-862) were consistent with those seen in the Phase 0 study [100]. Similar to results from CTEP Study 7675 (A06-161), Veliparib absorption and elimination were relatively rapid after administration of Veliparib alone on Day 7. Across Study M06-862 subjects, the time to the maximum concentration (Tmax) averaged 1.2 hours and the predose concentration averaged 27%
of the maximum concentration (Cmax). The coefficients of variation in dose-normalized Cmax and area under the curve (AUC) over a dosing interval (AUC0-12) on Day 7 were 40% and 50%, respectively. Veliparib 40 mg twice daily (BID) produced an average steady-state AUC0-24 of 4.81 µg•hr/mL, assuming equivalent AUCs following the morning and evening doses. This clinical regimen exposure is comparable to that associated with the maximally effective Veliparib regimens in murine efficacy models (3.0 µg•hr/mL). Across the dose range studied, Veliparib Cmax and AUC were approximately dose-proportional with minimal accumulation of plasma Veliparib concentrations following BID dosing. Additionally in Study M06-862, the potential pharmacokinetic interaction between Veliparib and temozolomide is being assessed by determination of the pharmacokinetics of temozolomide and Veliparib when administered alone on Days 1 and 7, respectively, and when co-administered on Day 3. At the dose levels studied to date, there is no indication of a significant pharmacokinetic interaction between Veliparib and temozolomide. Preliminary Veliparib pharmacokinetics in another Phase 1 Study M10-128 show trends of approximately dose-proportional pharmacokinetics and absence of a significant food effect. Preliminary safety and/or efficacy results are available from 5 Phase 1, 1 Phase 1/2, and 4 Phase 2 Abbott-sponsored studies of Veliparib in combination with a DNA-damaging agent [100]. In the Phase 1 Study M06-862, doses in the dose-escalation portion of the study ranged from 10 mg Veliparib BID/150 mg/m2temozolomide once daily (QD) to 80 mg Veliparib BID/200 mg/m2 temozolomide QD. No DLTs were reported for the first 3 dose-escalation cohorts (10, 20, and 40 mg Veliparib BID). In cohorts receiving 60 and 80 mg BID, events of grade 4 neutropenia or thrombocytopenia were reported. The MTD combination dose was defined as 40 mg Veliparib BID/200 mg/m2temozolomide QD. In addition to defining the MTD, a second dose, lower than the MTD but also predicted to be biologically active, was defined as 20 mg Veliparib BID/200 mg/m2temozolomide QD. Although no DLTs were reported in Study M06-862 subjects in the 40 mg Veliparib BID 200 mg/m2temozolomide QD dose-escalation cohort, 2 subjects enrolled at the same dose in the expanded MTD safety cohort experienced serious adverse events of grade 4 neutropenia and/or thrombocytopenia, and 8 of all 12 subjects receiving 40 mg Veliparib BID 200 mg/m2 experienced grade 3 or 4 adverse events of neutropenia and/or thrombocytopenia. In general, subjects with these events recovered after dose reduction of Veliparib and/or temozolomide, and all subjects remained on study. To minimize these hematologic toxicities, Study M06-862 protocol was modified to treat new subjects with 40 mg Veliparib BID in combination with 150 mg/m2 temozolomide QD in the first cycle. If a subject did not experience grade 3 or 4 neutropenia or thrombocytopenia or other clinically significant NCI CTCAE greater than grade 3, the temozolomide dose was escalated to 200 mg/m2 QD. In addition to neutropenia and thrombocytopenia, the other most commonly reported adverse events in Study M06-862 occurring in ≥ 30% of subjects were nausea, fatigue, vomiting, constipation, decreased appetite, and headache. All of the most commonly reported adverse events have previously been reported in subjects receiving temozolomide. For Study M06-862, preliminary data on tumor assessment was available for 42 subjects. Two of 42 subjects (4.76%) experienced an objective partial response. Of these, one subject, a BRCA-deficient ovarian cancer patient, experienced an objective partial response in Cycle 6 and this partial response was confirmed in Cycles 8 and 10. The other, a subject with hepatocellular carcinoma (HCC), experienced a partial response in Cycle 4 that was confirmed in Cycles 6, 8, 10, and the Final Visit. In the Phase 1/2 Study M10-190, Veliparib was administered in combination with radiation therapy with concurrent and adjuvant temozolomide (75 mg/m2for 6 weeks). Preliminary safety data were available for 18 subjects. The most commonly reported adverse events occurring in ≥ 30% of subjects were nausea, fatigue, headache, insomnia, and thrombocytopenia. Study M10-440 is a Phase 2 randomized, double blind, placebo-controlled study of Veliparib (20 or 40 mg BID) in combination with temozolomide (150 mg/m2/day with possible escalation to 200 mg/m2). This study is fully enrolled and ongoing. Preliminary blinded safety data are available for 344 subjects. The most common AEs (reported in ≥ 30% of subjects receiving Veliparib plus temozolomide) were nausea, fatigue, constipation, thrombocytopenia, and vomiting. In the Phase 2 Study M10-757, preliminary safety data are available for 165 subjects. The most common treatment-emergent AEs (reported for ≥ 30% of subjects receiving Veliparib plus temozolomide at any point) reported in subjects with recurrent high-grade serous ovarian cancer treated with Veliparib plus with temozolomide versus PLD alone, were nausea, fatigue, thrombocytopenia, vomiting, constipation, neutropenia, and decreased appetite. Preliminary efficacy data are not yet available. Preliminary safety data are available for 26 subjects. The most common treatment-emergent AEs (≥ 30% of all subjects) reported in Study M11-070, a trial evaluating subjects with metastatic castration-resistant prostate cancer treated with Veliparib plus temozolomide, were fatigue, nausea, and platelet count decreased. Preliminary data on maximum percentage reduction from baseline in PSA values are available for 25 subjects. Confirmed PSA responses have been observed in 2 subjects. The mean (SD) for the largest observed decrease from baseline in PSA values was 11.7% (48.3%). In an extension study of Study M11-846, preliminary safety data available are for 23 subjects. The most common treatment-emergent AEs (≥ 30% of all subjects) reported in Study M12-273, a trial evaluating subjects with solid tumors treated with Veliparib plus temozolomide, were nausea, fatigue, vomiting, abdominal pain, decreased appetite, and thrombocytopenia. No preliminary efficacy data are available.
appendix h example tumor variant
appendix j azd1775 (proprietary information)

AZD1775 is a selective, adenosine-triphosphate (ATP) competitive, small molecule inhibitor of Wee1 kinase (IC50 = 5.18 nM), that directly inhibits phosphorylation of CDC2 at Tyr15. The antitumor effect of AZD1775 in combination with carboplatin was investigated in the HeLa-luc (human cervical adenocarcinoma) nude rat xenograft model. AZD1775 was administered orally to the animals 24 hr after carboplatin (50 mg/kg: MTD) at doses of 10, 20 and 30 mg/kg; single IV bolus treatments of carboplatin showed significant antitumor efficacy with %T/C = 70%. Tumor growth was not inhibited by AZD1775 monotherapy at a dose of 30 mg/kg, with %T/C = 96%. AZD1775 dose-dependently enhanced the anti-tumor effect of carboplatin in HeLa-luc tumors with %T/C = 85, 39 and 28% at doses of 10, 20 and 30 mg/kg, respectively. AZD1775 did not cause significant enhancement of carboplatin-induced reduction of WBC (38 - 45% control) and platelets (15 - 26% control), and these parameters returned to normal by Day 20 and 10 in the combination arms. AZD1775 alone did not show severe blood cell toxicity. No severe body weight loss (-2 to -5% delta change vs. control), abnormal physical signs or mortality were observed in any treatment group. These results suggest that the combination of AZD1775 with carboplatin has anti-tumor efficacy and is well tolerated. An additional tolerability study was conducted in non-tumor bearing nude rats dosed with carboplatin alone or in combination with AZD1775 over multiple cycles. Doses of carboplatin (50 mg/kg IV), alone and in combination with AZD1775 (20 mg/kg orally, 24 hrs after carboplatin dosing), were administered once during a 28-day cycle for 3 consecutive cycles. Body weight and blood cell counts were monitored during the study period. There were no significant changes in toxicity parameters between the carboplatin alone and the carboplatin + AZD1775 treatment arms. Thus, AZD1775 did not significantly enhance the toxicity parameters of carboplatin when used in the multi-cycle dosing schedule.
appendix h example tumor variant
non-clinical toxicology

The toxicology profile of AZD1775 in rats involved the lymphoid and hematopoietic organs and gastrointestinal tract, and included decreased food consumption, body weight loss, hematologic and serum chemistry changes, decreased urine volume and soft feces. AZD1775 had no effect on CNS function in mice. The cardiovascular effects of AZD1775 were examined in 5 isofluraneanesthetized and mechanically vented dogs. At doses of 3 and 10 mg/kg, QTc was marginally prolonged by an average of 5% and 7%, respectively. No QTc changes were observed in the intact dog studies or human studies. Evidence of reversibility of all toxicity changes was generally demonstrated by the end of the 2-week recovery period. In a single dose oral toxicity study, severe irreversible toxicity (mortality) was seen in 1 female out of 10 female rats after a single dose at 300 mg/kg (1800 mg/m2). Based on the preliminary safety data available, the most frequent AEs observed were blood and lymphatic disorders (thrombocytopenia, neutropenia, anemia, febrile neutropenia), gastrointestinal disorders (diarrhea, vomiting, nausea, abdominal pain, constipation), and investigation findings (hematology and serum chemistry). The single-dose TD for both the gemcitabine and cisplatin combination therapies was 200 mg of AZD1775. DLTs tended to be hematological in nature in the gemcitabine group and constitutional in the cisplatin group. The single-dose MTD for the combination with carboplatin was 325 mg of AZD1775. DLTs in this group were related to serum chemistry.
appendix h example tumor variant
clinical studies

AZD1775 has been administered to patients in 12 AstraZeneca-sponsored or Merck-sponsored clinical studies, 6 of which are ongoing. Completed or terminated early:
- PN001 (NCT00648648): a first-time-in-patients (FTIP), Phase I, dose-escalation study evaluating AZD1775 both as monotherapy and combination therapy with gemcitabine, cisplatin, or carboplatin in adult patients with advanced solid tumours
- PN004 (NCT01357161): a Phase II study evaluating AZD1775 combined with carboplatin and paclitaxel in patients with platinum-sensitive p53-mutant ovarian cancer
- PN005 (NCT01047007): a Phase I, dose-escalation study evaluating AZD1775 as monotherapy (Part 1), combination therapy with 5-FU (Part 2), and combination therapy with 5-FU plus cisplatin (Part 3) in adult Japanese patients with advanced solid tumours was terminated early due to portfolio prioritisation in oncology at Merck after 3 patients had been enrolled in Part 1 and 8 patients had been enrolled in Part 2. Part 3 was not initiated.  
- PN008 (NCT01076400): a Phase I/IIa, dose-escalation study evaluating AZD1775 in combination with topotecan plus cisplatin in adult patients with cervical cancer was terminated early due to portfolio prioritisation in oncology at Merck after 7 patients had been enrolled in the dose-escalation part of the study. The Phase IIa part was not initiated.  
- D6011C00001 (NCT02087176; SCRI LUN 262): a lead-in Phase II multicentre, randomised, double-blind study comparing AZD1775 plus docetaxel with placebo plus docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC)
- D6011C00002 (NCT02087241; SCRI LUN 261): a Phase II study of AZD1775 plus pemetrexed and carboplatin followed by a randomised comparison of pemetrexed and carboplatin with or without AZD1775 in patients with previously untreated stage IV nonsquamous NSCLC.  
Ongoing:
- D6010C00004 (NCT02272790; SCRI GYN 49): multicentre Phase II study of AZD1775 plus either paclitaxel, gemcitabine, carboplatin, or pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer
- D6010C00005 (NCT02511795; SCRI REFMAL 384): Phase I study evaluating AZD1775 in combination with olaparib in refractory solid tumours.  
- D6011C00003 (NCT02341456): Phase Ib dose-finding study evaluating AZD1775 as monotherapy and in combination with carboplatin and paclitaxel in adult Asian patients with advanced solid tumours
- D6015C00001 (NCT02482311; SCRI REFMAL 383): Phase I, dose escalation, safety and pharmacokinetic study of AZD1775 monotherapy (Schedule 1) in patients with advanced or metastatic solid tumours
- D6015C00002 (NCT02617277; SCRI REFMAL 412): Phase I study assessing the safety, tolerability, and pharmacokinetics of AZD1775 in combination with MEDI4736 in patients with advanced solid tumours
- D6015C00003 (NCT02610075; SCRI REFMAL 398): Phase Ib study to determine the maximum-tolerated dose (MTD) of AZD1775 monotherapy (Schedule 2) in patients with locally advanced or metastatic solid tumours.  
- In addition, Phase I and II studies are being conducted and sponsored by the National Cancer Institute's (NCI) Cancer Therapy Evaluation Program, and by several other institutions as investigator-sponsored studies.  
As of 11 November 2016, a total of approximately 551 patients have been exposed to AZD1775 in AstraZeneca-sponsored or Merck-sponsored clinical studies. Of these 551 patients, 103 received AZD1775 monotherapy, 407 patients received AZD1775 in combination with cytotoxic chemotherapy agents and the remaining 41 patients received AZD1775 in combination with targeted therapies MEDI4736 or olaparib. In addition, approximately 350 patients have also received AZD1775 as part of externally-sponsored scientific research. These patients have received single doses per cycle as high as 1300 mg of AZD1775 as monotherapy, 325 mg of AZD1775 in a single-dose in combination with chemotherapy, and 325 mg twice a day (BID) in a multiple-dose regimen in combination with chemotherapy. The PK data of AZD1775 following a single oral administration showed a moderate rate of absorption with a Tmax occurring at 3 to 4 hours. Post-peak plasma concentrations declined essentially in a mono-exponential manner with a t1/2 in the region of 10 hours. Exposure as measured by maximum plasma drug concentration observed (Cmax) and AUC0-∞ increased in a dose-proportional manner over the dose range of 325 to 1300 mg. Following single (100 to 325 mg) and multiple dose administrations of AZD1775 (25 to 325 mg BID and 100 to 200 mg once daily [QD]) with carboplatin, cisplatin, and gemcitabine, plasma exposure of AZD1775 was consistent with predictions based on the single-dose regime. Preliminary investigation of drugdrug interactions in Study PN001 suggest a 40% to 60% increase in the exposure of AZD1775 in the presence of aprepitant (moderate CYP3A4 inhibitor), but no effect with the concomitant administration of various different corticosteroids (moderate CYP3A4 inducers). Preliminary studies also suggested that the PMF of AZD1775 was similar to that of the FFP formulation. Based on the safety data from the 3 completed AZD1775 clinical studies and preliminary data from ongoing studies, the most frequent adverse events (AEs) observed were blood and lymphatic disorders (leukopenia, lymphopenia, neutropenia, thrombocytopenia, anaemia, febrile neutropenia, pancytopenia), gastrointestinal disorders (diarrhoea, vomiting, nausea, abdominal pain, constipation), general disorders and administration site conditions (fatigue, fever, chills), and investigation findings (haematology and serum chemistry). Cardiac disorders (tachycardia, palpitations, QTc prolongation) were not observed frequently, but are considered to be important identified risks. Gastrointestinal haemorrhage is considered an important potential risk to be monitored closely as the programme progresses. Based on the safety data from the completed AZD1775 clinical studies and preliminary data from ongoing studies adverse drug reactions to AZD1775 monotherapy include: anaemia, neutropenia, thrombocytopenia, QTc prolongation, gastrointestinal events such as dyspepsia, diarrhoea, nausea and vomiting (with or without dehydration or serum electrolyte decreases), as well as decreased appetite. In addition, the following events are also considered expected during treatment with AZD1775 in combination with cytotoxic chemotherapy: febrile neutropenia, leukopenia, stomatitis, asthenia, fatigue, mucosal inflammation and myalgia. Based on information emerging during the clinical development programme of AZD1775, potential risks with AZD1775 monotherapy include asthenia/fatigue, febrile neutropenia, gastrointestinal haemorrhage, lymphopenia/lymphocyte count decreased, leukopenia/WBC count decreased, myalgia, stomatitis, sepsis and transaminases elevation. In addition, the following events are also considered potential risks for AZD1775 in combination with cytotoxic chemotherapy: tachycardia and pancytopenia. Refer to the IB for AZD1775 for information on the potential benefits and assessment of potential and known risks. In Study PN001, of 176 evaluable patients who received AZD1775 (either single or multiple doses) as monotherapy or in combination with gemcitabine, cisplatin, or carboplatin, a partial response (PR) (confirmed and unconfirmed) was observed in 17 (9.7%) patients, and stable disease (SD) was observed in 94 (53.4%) patients. No complete responses (CRs) or PRs were observed in either of Studies PN005 or PN008 at the time that they were terminated. In Study PN004, all patients were treated at the 225 mg AZD1775 BID 2.5 day dose level in combination with paclitaxel and carboplatin. Of the 14 evaluable patients by RECIST v1.1 in Part 1, there were 11 PRs (6 confirmed and 5 unconfirmed), and 3 SDs; 7 patients were evaluable by CA-125 with 3 CRs and 4 PRs. Final data for Part 2 was not available as of the cut-off date for this brochure. In Study D6011C00001, 32 patients with NSCLC were treated with 225 mg AZD1775 BID over 2.5 days in combination with docetaxel (75 mg/m2 IV) administered on Day 1 followed by pegfilgrastim on Day 4 of each 21-day cycle. The 3 patients (9.4%) that achieved PR by RECIST v1.1 had TP53 mutations. Twenty-one patients (65.6%) had SD and 10 (47.6%) of these patients had TP53 mutations. The planned Interim Analysis of 32 patients in the single cohort lead-in (Part A) suggested that toxicities associated with AZD1775 given in combination with docetaxel were greater in frequency and severity than with docetaxel alone. Additionally, the analysis revealed that it was very unlikely the target response rate would be reached in this study and a decision was made to terminate enrolment. In Study D6011C00002, 14 patients with NSCLC were treated with 225 mg AZD1775 BID over 2.5 days in combination with pemetrexed 500 mg/m2 IV and carboplatin AUC 6 IV, both administered on Day 1 of each 21-day cycle. Enrolment was stopped because of the introduction of new therapies for the treatment of first-line NSCLC, such as immunotherapy, which resulted in challenges in patient recruitment. In addition, the planned Interim Analysis of Study D6011C00001 revealed that it was very unlikely that the target response rate would be reached, and increased gastrointestinal and hematologic toxicities associated with AZD1775 were observed.
appendix h example tumor variant
clinical pharmacokinetics

The major metabolic pathway of AZD1775 in human liver preparations is oxidative metabolism. Oxidative metabolism of AZD1775 is mediated predominantly by cytochrome P450 (CYP) 3A4 and FMO3. AZD1775 is also a weak reversible inhibitor of CYP2C8, CYP2C9, CYP2C19 and CYP3A4. In addition, AZD1775 is a time-dependent inhibitor of CYP3A4 in *in vitro* human liver microsomes.
appendix h example tumor variant
appendix k trametinib dmso (proprietary

Trametinib DMSO is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation and kinase activity. The safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and activity of trametinib DMSO are currently being evaluated in 13 ongoing monotherapy and combination therapy clinical trials involving subjects with a variety of cancers. In May 2013, the FDA approved trametinib DMSO for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E or BRAFV600K mutations. In January 2014, the FDA also granted accelerated approval to the combination of trametinib DMSO and dabrafenib to treat patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations.
appendix h example tumor variant
nonclinical pharmacology

MEK proteins are critical components of the extracellular signal-related kinase (ERK) pathway which is commonly hyperactivated in tumor cells. Oncogenic mutations in both B-RAF and RAS signal through MEK1 and MEK2. Trametinib DMSO is non-competitive towards ATP and inhibits activation of MEK by RAF kinases as well as MEK kinase activity. The specificity of trametinib DMSO to MEK1 and MEK2 was confirmed against a panel of 183 kinases, including MEK5, the closest kinase homolog to MEK1 and MEK2, and no significant inhibitory activity was measured [101]. In vitro, 80% of cell lines carrying activating mutations of B-Raf and 72% of Ras mutant cancer cell lines were sensitive to trametinib DMSO in cell proliferation assays, and a majority (83%) of hematopoietic cancers from acute or chronic myeloid leukemia (AML or CML, respectively) origins were also very sensitive.
appendix h example tumor variant
antitumor activity in vitro

Cancer cells expressing high constitutive levels of activated ERK (pERK) tended to be more sensitive to trametinib DMSO than those with lower levels of pERK, suggesting that tumors with B-RAF or RAS mutations and/or high levels of pERK may respond to trametinib DMSO treatment. In all cell lines, pERK was strongly inhibited following treatment with trametinib DMSO and was independent of their proliferative response, suggesting that pERK inhibition is necessary but not sufficient to inhibit cell proliferation. In cell lines that were sensitive to the anti-proliferative activity of the agent, the response was associated with arrest in G1 phase of the cell cycle, accumulation of p27, reduction of cyclin D1 and phospho-retinoblastoma protein. Induction of apoptosis was demonstrated in some cell lines. Inhibition of pERK and inhibition of cancer cell proliferation were fully reversible following compound removal, suggesting that sustained exposure to trametinib DMSO, or potential combination with other drugs, may be required for full activity. When trametinib DMSO was combined with standard of care drugs against human cancer cell lines in vitro, an additive effect was observed for pancreatic cancer with gemcitabine or erlotinib and for colon cancer with 5-FU or irinotecan. The combination of trametinib DMSO with rapamycin, ara-C, bexarotene or sorafanib produced an additive effect against most AML cell lines tested. In addition, combination of agent with an investigational phosphoinositide 3-kinase (PI3K) inhibitor, as well as with a Centromer Protein-E (CENP-E) inhibitor, was synergistic on inhibition of cell growth in various cancer (pancreas, colon, lung) cells. Additionally, the combination of trametinib DMSO and a CENP-E inhibitor increased caspase activity, indicating enhanced apoptosis in colon cancer cell lines. While many proliferating human cells are sensitive to trametinib DMSO in vitro, the agent did not affect non-dividing normal cells and did not completely inhibit bone marrow progenitor cells at concentrations demonstrating anti-proliferative activity on very sensitive cancer cell lines.
appendix h example tumor variant
antitumor activity in vivo

Trametinib DMSO was orally bioavailable in mice, and doses as low as 1 mg/kg reached blood concentrations that caused sustained reductions of pERK, an accumulation of p27, and a decrease of Ki67 in tumor xenografts; brain exposure levels were ~10% of those in blood, and no significant pERK inhibition was measured in brain tissue. In mice, exposure to trametinib DMSO produced dose- and schedule-dependent anti-tumor responses correlating with blood levels. Typically, B-RAF--mutant xenografts responded with tumor regression while K-RAS-mutant xenografts responded with tumor growth inhibition. In vivo combination studies testing trametinib DMSO together with various other anticancer drugs showed good potential for synergistic effects.
appendix h example tumor variant
safety pharmacology

In a rat neurobehavioral screen, following a single oral dose of trametinib DMSO at 650 mg/m2to male rats, diarrhea, prone position, blepharoptosis, piloerection, reduced spontaneous locomotion and mydriasis were observed between 2 and 24 hours post dose. In a respiratory safety pharmacology study in rats, an oral dose of 1 mg/m2 produced a mild, transient decrease in body temperature (up to 0.8°C) at 1 hour post dose. There were no other effects on ventilatory function, airway resistance or body temperature. Trametinib DMSO inhibited hERG channel repolarization in HEK293 with an IC50 of 1.54 μM (950 ng/mL). In a rabbit left ventricular wedge assay, trametinib DMSO had no significant effect on QT interval at concentrations up to 30 μM (18450 ng/mL; limit of solubility). However, significant decreases in isometric contractile force occurred at concentrations of 10 (6150 ng/mL) and 30 μM. Trametinib DMSO also decreased the Tp-e interval at a concentration of 30 μM. A single intravenous infusion of drug in dogs at 20 mg/m2 over 10 minutes (Cmax of 2.5 μM or 1500 ng/mL) produced no changes in electrocardiogram (ECG) parameters, blood pressure, or heart rate during the 30 minute measurement period. In addition, single oral doses up to 1.5 mg/m2in dogs produced no changes in arterial blood pressure, heart rate, body temperature, or ECG intervals, including QTc. While trametinib DMSO affected cardiac electrophysiology in vitro, no effects were observed in vivo at doses that were maximally tolerated in dogs. This difference in responses is likely related to the very low Cmax (~10 ng/mL total drug) at tolerated doses in dogs and the high protein binding (97% in dogs) of agent. The concentrations at which effects were seen in these in vitro studies are significantly higher than the free fraction observed in nonclinical toxicology studies or the clinical dose (2 mg). These results suggest a low risk for cardiovascular effects in the clinic.
appendix h example tumor variant
pharmacokinetics and product metabolism in

Trametinib DMSO exhibited low plasma clearance among nonclinical species (mouse, rat, dog and monkey) with varied but generally long half-lives. Oral bioavailability ranged between 42% and 100%. Since trametinib DMSO is a low solubility, high permeability molecule, its absorption is likely limited by solubility and dissolution. Plasma protein binding was high in nonclinical species and human (>95%) and blood cell association was low. Consistent with high permeability, trametinib DMSO had moderate to high volume of distribution among the nonclinical species studied and DRM was widely distributed into rat tissues. The low concentration of DRM observed in the brain up to 8 hours post dose was observed. Although studies showed protracted elimination of DRM (consistent with high volume and long half-life), DRM in tissues was not detectable by 35 days post dose. In rats and dogs after repeat oral dosing up to 13 weeks, systemic exposure increased approximately dose-proportionally at higher doses or when steady state was reached at Week 3. Upon repeat dosing, increases in systemic exposure after Day 1 were observed up to Week 3; however, between Weeks 4 and 13, there was no marked increase in systemic exposure for either pre-clinical species. A tendency for higher exposure in females than in males was observed in some studies in both rats and dogs. No apparent human-specific metabolite was observed in the in vitro cross-species [14C] trametinib DMSO metabolism study. [
14C] trametinib DMSO was also found to metabolize predominantly via a non-cytochrome P450 (CYP) mediated deacetylation with secondary oxidation or glucuronidation biotransformation pathways. CYP3A4 was implicated in the in-vitro formation of M7, a metabolite mediated by both non-CYP and CYP pathways. The relative contribution of CYP3A4 to the total metabolic clearance of trametinib DMSO in human in vivo is not currently understood and, therefore, the possibility of a metabolic drug interaction cannot be eliminated. Elimination of DRM in rat and dog after oral administration occurred predominantly via the feces (>60% of dose), with urinary excretion (<7% of dose) representing a minor route. Trametinib DMSO is metabolized predominantly via deacetylation (non-cytochrome P450 [CYP450]-mediated) with secondary oxidation or in combination with glucuronidation biotransformation pathways (Investigator's Brochure, 2012). Deacetylation is likely mediated by hydrolytic esterases, such as carboxylesterases, or amidases. Based on *in vitro* studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4. Trametinib DMSO has an overall low potential for drug-drug interactions. There was no evidence of time-dependent inhibition with any of the CYP enzymes investigated.
appendix h example tumor variant
toxicology

Systemic toxicity of trametinib DMSO has been evaluated following oral dosing in rats and dogs for up to 13 weeks. In the most sensitive nonclinical species, rat, the principal adverse effects seen in oral toxicity studies of up to 13 weeks with daily dosing were skin and stomach erosions, skin ulcerations, which were secondary to reduced proliferation, altered phosphate homeostasis that resulted in soft tissue mineralization, hepatocellular necrosis, bone marrow degeneration/necrosis and ovarian perturbations. The skin and stomach findings and phosphatemia demonstrated reversibility with 4 weeks of recovery. MTD in rats in the definitive 13 week study with daily dosing was 0.25 mg/m2/day (AUC0-t of 126 ng.h/mL, end of study). Reversible acute effects (diarrhea, decreased body weight gain, prone position, blepharoptosis, piloerection, reduced spontaneous locomotion and mydriasis) were observed following a single high dose of 650 mg/m2to rats. In dogs, the principal dose-limiting toxicities seen oral toxicity studies of up to 13 weeks with daily dosing were related to gastrointestinal and hematopoietic perturbations. Inflammatory responses to gastrointestinal erosions were observed in dogs and were reversible following a recovery period. In the definitive 13 week daily oral dosing study in dogs, the NOAEL was 0.45 mg/m2/day (AUC0-t of 139 ng.h/mL, end of study). Principal adverse effects were consistent with inhibition of cell proliferation and were monitorable and generally reversible. Trametinib DMSO was negative in both in vitro and in vivo genotoxicity assays.
appendix h example tumor variant
effects in humans

The effect of Trametinib DMSO in subjects with a variety of refractory cancers is currently under evaluation in 14 clinical studies. As of 14 April 2011, 657 subjects with cancer have received at least one dose of trametinib DMSO in the ongoing Phase I/II/III clinical studies. There are no completed clinical trials to date. Preliminary trametinib DMSO pharmacokinetics were determined after single- and repeat dose oral administration of tablets in subjects with solid tumors. Trametinib DMSO is absorbed rapidly with median Tmax generally occurring within 1-3 hours after oral administration under fasting conditions. Following repeat-dosing the mean area under the curve (AUC0-τ) and maximum concentrations(Cmax) increased in an approximately dose proportional manner. Trametinib DMSO accumulates with repeat dosing with a mean effective half-life of approximately 5 days. The MTD was established at 3.0 mg once daily (QD), and the recommended Phase II dose was identified as 2.0 mg QD.  
| Phase                                     | Study #                            | Treatment Regimen                                                                     | Study Population                    |
|-------------------------------------------|------------------------------------|---------------------------------------------------------------------------------------|-------------------------------------|
| Monotherapy Studies  I MEK111054          | Single agent (First-time-in-human) | Solid tumors and BRAFmutant melanoma                                                                                       |                                     |
| I/II                                      | MEK111759                          | Single Agent                                                                          | Leukemia                            |
| II                                        | MEK113583                          | Single agent                                                                          | BRAF-mutant Melanoma                |
| III                                       | MEK114267                          | Randomized comparison GSK1120212 vs.                                                  | BRAF-mutant melanoma                |
| chemotherapy (dacarbazine, or paclitaxel) |                                    |                                                                                       |                                     |
| MEK113708                                 | Phase I ADME study                 | Solid tumors                                                                          |                                     |
| MEK113709                                 | Phase I Food-Effect study          |                                                                                       |                                     |
| Combination Therapy Studies  IB/II MEK112110 Combination with everolimus (mTORinhibitor)                                           | Solid tumors                       |                                                                                       |                                     |
| I/IB                                      | MEK112111                          | Combination with gemcitabine                                                          | Solid tumors and pancreatic  cancer |
| Multi-arm combination with docetaxel,     |                                    |                                                                                       |                                     |
| I/IB                                      | MEK113486                          | pemetrexed, pemetrexed/carboplatin, nabpaclitaxel, or erlotinib                                                                                       | Solid tumors                        |
| I                                         | MEK114784                          | Single agent and combination with                                                     | Japanese subjects with solid        |
| gemcitabine                               | tumors                             |                                                                                       |                                     |
| I/II                                      | BRF113220                          | Combination with GSK2118436 (BRAFinhibitor)                                                                                       | BRAF-mutant melanoma                |
| I                                         | TAC113886                          | Combination with GSK214795 (AKTinhibitor)                                                                                       | Solid tumors                        |
| I                                         | P3K113794                          | Combination with GSK2126458 (PI3                                                      | Advanced solid tumors               |
| Kinase-inhibitor)                         |                                    |                                                                                       |                                     |
| II                                        | MEK113487                          | Randomized combination GSK1120212 with  gemcitabine vs. gemcitabine Pancreatic cancer |                                     |
appendix h example tumor variant
safety/tolerability profile

The maximum tolerated dose was established at 3 mg daily. The safety profile at doses greater than 2 mg QD was not as favorable with a larger percent of subjects with Grade 2 rash, rash leading to dose reduction, peripheral edema, and cardiac failure. A dose of 2 mg QD was selected to minimize need for dose reduction and allow subjects to receive the highest dose that is well tolerated. The most common AEs experienced following 2 mg daily are diarrhea, rash, nausea, fatigue, vomiting, anemia, peripheral edema, abdominal pain, constipation, dermatitis acneiform, decreased appetite, pruritus, dyspnea, pyrexia, pneumonia, febrile neutropenia, AST increased, ALT increased, and dry skin. Other clinically important adverse reactions observed in ≤10% of patients (n=329) treated with trametinib were: nervous system disorders (dizziness, dysgeusia), ocular disorders (blurred vision, dry eye), infections and infestations (folliculitis, rash pustular, cellulitis), cardiac disorders (bradycardia), gastrointestinal disorders (xerostomia), and musculoskeletal and connective tissue disorders (rhabdomyolysis).
appendix h example tumor variant
appendix l nci correlative imaging

Patients at the NCI will be asked to sign a separate consent to allow collection and use of the standard-of-care images (CT or MRI) that qualified the patient for inclusion in this trial, along with the images taken during image-guided biopsy and any follow up imaging studies showing progression, to allow research into correlation of the image phenotypic features with genomic analyses. Research analysis of these images will only be done once the images have been de - identified; no research data generated from any image will be reported back to the patient, and no clinical decisions will be made based on research data generated from any image collected under this protocol. To accomplish delinking, the NCI's secure GeneMed bioinformatics database will assign an imaging ID that, initially, will be coupled with the MPACT protocol ID in the GeneMed database. When a patient is off-study, GeneMed will provide the limited clinical information from that patient to the Cancer Imaging Archive (TCIA), linked through the imaging ID (not the patient protocol ID). GeneMed will assign a new ID that will trigger permanent recoding of the physical tissue, which will undergo whole exome sequencing. Following recoding, all samples and images will be completely unlinked from the clinical database. Patient images will be de-identified of PHI at the CCR Molecular Imaging Program before leaving the NIH Clinical Center site and stored in an NIH policy compliant internet-accessible collection, The Cancer Imaging Archive (TCIA), with controlled access. Images for TCIA are processed at the clinical site through a program developed by the Radiological Society of North America and NCI called the Clinical Trials Processor (CTP) [102]. Images are directly sent to the TCIA where they are sequestered pending, as needed, further QC/QA and appropriate sponsor access approvals. The individual responsible for this process is Justin Kirby (kirbyju@mail.nih.gov). The CTP is the primary means for uploading images into TCIA. CTP is a client-server software package with the server installed on a special intake system at TCIA. The CTP client, containing de-identification scripts customized for the trial site and specific trial data collection, will be installed in the Molecular Imaging Program in CCR. The Digital Imaging and Communications in Medicine (DICOM) image is sequestered in TCIA pending review, QC/QA, and sponsor permission to link to genomic and limited clinical data after it has been delinked from the patient identifiable data.  
The de-identification process follows the DICOM WG18 Supplement 142 standard. The following are examples of the changes made:
- Patient Names - Real patient names and initials are removed.  
- Patient IDs - Institutionally created patient identifiers that can be traced back to individual patients are replaced with another unique identifier that cannot be traced back to the patient.  
- Patient Demographics - Although patient date of birth is removed, patient age and gender are retained.
- Dates related to the examination - For a given collection/site, dates are offset by a fixed number of days, preserving time intervals between exams for each subject.  
- Exam Identifiers - Codes assigned to exams and images are altered to prohibit the possibility of tracing an exam back to an institution and individual patient.  
As part of the QC/QA process TCIA will also review submitted images for vendor specific DICOM tags. Vendor DICOM Conformance Statements are reviewed to learn which tags might contain PHI. These tags are reviewed and PHI removed if found.