untitled h1
appendix d cyp3a4 cyp2c8 and

NOTE: This is a selected listing of strong and moderate CYP3A4, CYP2C8, and CYP3A4 inducers and inhibitors for this trial.  
CYP3A4 Strong Inhibitors (1/2 life): Chloramphenicol (4hrs), Clarithromycin(3-7hrs), Itraconazole (21 hrs single dose, 64 hrs steady state), Ketoconazole (systemic) (2-8hrs), Nefazodone(2-4hrs), Telithromycin(10hrs), Voriconazole (dose-dependent) CYP3A4 Strong Inducers (1/2 life): Barbituates (variable), Carbamazepine (25-65 hrs), Phenytoin (7-42 hrs), Rifampin (3-4 hrs), St. John's Wort (9-43 hrs)
CYP2C8 Strong Inhibitors (1/2 life): Gemfibrozil (1-2 hrs), Montelukast (3-6 hrs), Quercetin (<2 hrs), Rosiglitazone (16-24 hrs) CYP2C8 Strong Inducer: Rifampin (3-5 hrs)
- FDA. "Drug Development and Drug Interactions: Table of Substrates, Inhbitors, and Inducers"(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResour ces/DrugInterac tionsLabeling/ucm093664.htm\#potency).  
- EMA. "Guideline on the investigation of drug interactions"
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeli ng/ucm093664.htm\#potency).  
- Strong CYP3A inhibitors are defined as those drugs that increase the AUC of oral midazolam or other CYP3A substrates > 5 fold. Ritonavir, indinavir, nelfinavir, atazanivir, and saquinavir are also strong CYP3A3 inhibitors, but would not be used in this study as patients with known HIV are excluded.  
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD
Protocol Chairs:  Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB)  
| Table 1:|                                                 | Examples of clinical substrates for CYP3A-mediated metabolism   |
|-----------------------------------------------------------|-----------------------------------------------------------------|
| Sensitive                                                 | Moderate Sensitive                                              |
| (AUC increase 25-fold with strong index inhibitor)        | (AUC increase 2 to 5-fold with strong index inhibitor)          |
| alfentanil, avanafil, buspirone, conivaptan, darifenacin, | alprazolam, aprepitant, atorvastatin", colchicine,              |
| darunavir , ebastine, everolimus, ibrutinib, lomitapide,  | eliglustat', pimozide, rilpivirine, rivaroxaban, tadalafil      |
| lovastatin", midazolam, naloxegol, nisoldipine,           |                                                                 |
| saquinavir", simvastatin", sirolimus, tacrolimus,         |                                                                 |  
  
tipranavir', triazolam, vardenafility budesonide, dasatinib, dronedarone, eletriptan, eplerenone, felodipine, indinavir', lurasidone, maraviroc, quetiapine, sildenafil, ticagrelor, tolvaptan Note: Sensitive substrates are drugs that demonstrate an increase in AUC of 25-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Modemte sensitive substrates are drugs that demonstrate an increase in AUC of 2 to <5-fold with strong index inhibitors of a given metabolic pathway in clinical DDI studies. Sensitive substrates of CYP3A with ≥10-fold increase in AUC by co-administration of strong index inhibitors are shown above the dashed line.  
Other elimination pathways may also contribute to the elimination of the substrates listed in the table above and should be considered when assessing the drug interaction potential.  
Abbreviations: AUC: area under the concentration-time curve; CYP: cytochrome P450; DDI; drug-drug interaction; OATP I B I : organic anion transporting polypeptide IBI.  
a Listed based on pharmacogenetic studies.  
b Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A.  
c Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor.  
d Acid form is an OATP1B1 substrate This table is propared to provide examples of clinical substrates and not intended to be an exhaustive list. DDI data were collected based on a search of the University of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. (2010), Hum Genomics, 5(1):61].  
Source:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.ht m\#table3-1 Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD
Protocol Chairs:  Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB)
untitled h1
appendix e md anderson symptom

M. D. Anderson Symptom Inventory - Brain Tumor (MDASI - BT)
Part I. How severe are your symptoms? People with cancer frequently have symptoms that are caused by their disease or by their treatment. We ask you to rate how severe the following symptoms have been in the last 24 hours. Please fill in the circle below from 0 (symptom has not been present) to 10 (the symptom was as bad as you can imagine it could be) for each item.  
  
  
o o o o  
  
o o o o o o  
  
As Bad As You  
  
D A P O I M E N
Copyright 2000 The University of Texas M. D. Anderson Cancer Center All rights reserved Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD
Protocol Chairs:  Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and  Erica Stringer-Reasor, MD (UAB)  
  
  
17. Your seizures at its WORST?  
  
| o   | o   | o   |
|-----|-----|-----|
| o   | o   | o   |
| o   | o   | o   |  
|  Not    |    |
|---------|----|
| Present |    |
| o       | 1  |
| o       | o  |
| o       | o  |
| o       | o  |
| o       | o  |  
| 2   | 3   | s   |
|-----|-----|-----|
| o   | o   | o   |
| o   | o   | o   |
| o   | O   | o   |
| o   | o   | o   |  
| o   | o   |
|-----|-----|
| o   | o   |
| o   | o   |
| o   | o   |
| o   | o   |  
o  
  
o o  
  
o  
  
| 7   |
|-----|
| o   |
| o   |
| o   |
| o   |
| o   |
| o   |  
o o o i netion. How much have your symptoms interfered o Copyright o D
Copyright 2000 The University of Texas M. D. Anderson Cancer Center All rights reserved  
| As Bad As You   |    |    |    |    |    |
|-----------------|----|----|----|----|----|
| Can Importe     |    |    |    |    |    |
| 5               | 6  | 7  | 8  | e  | 10 |
| o               | o  | o  | o  | o  | o  |
| o               | o  | o  | o  | o  | o  |
| o               | o  | o  | o  | o  | o  |
| o               |    |    |    |    |    |
| o               | o  | o  | o  | o  |    |
| o               | o  | o  | o  | o  | o  |  
| a   | 9   |
|-----|-----|
| o   | o   |
| o   | o   |
| o   | o   |
| o   | o   |
| O   | O   |
| o   | o   |  
| rolecely   |
|------------|
| 10         |
| o          |
| o          |
| o          |
| o          |
| o          |  
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD  
  
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)
appendix f linear analog self
appendix e md anderson symptom

Linear Analog Self Assessment (LASA): Quality of LifeAssessment Subject ID: Date: Directions: Please circle the number (0–10) best reflecting your response to the followingthat describes your feelings during the past week, includingtoday.  
1. How would you rate your physical well being over the pastweek?  
This question refers to such things as fatigue, activity, etc.  
0 1 2 3 4 5 6 7 8 9 10 (0= As bad as it can be; 10 = As good as it can be)
2. How would you rate your emotional well being over the past week?  
This question refers to such things as depression, anxiety, stress,etc.  
0 1 2 3 4 5 6 7 8 9 10 (0= As bad as it can be; 10 = As good as it can be)
3. How would you rate your spiritual well being over the past week?  
This question refers to such things as a sense of meaning and purpose, relationshipwith God, etc. 0 1 2 3 4 5 6 7 8 9 10 (0= As bad as it can be; 10 = As good as it can be)
4. How would you rate your intellectual well being over the past week?  
This question refers to such things as the ability to think clearly, to concentrate,to remember, etc. 0 1 2 3 4 5 6 7 8 9 10 (0= As bad as it can be; 10 = As good as it can be)
5. How would you rate your overall well being over the pastweek?  
0 1 2 3 4 5 6 7 8 9 10
(0= As bad as it can be; 10 = As good as it can be)
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD  
  
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)  
| Level of Function Score                                                                                                                                                                                                                                                                                                                                                                                   |                                                                     |                                                     |                                                                  |                                                |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|-----------------------------------------------------|------------------------------------------------------------------|------------------------------------------------|
| Domain                                                                                                                                                                                                                                                                                                                                                                                                    | 0                                                                   | 1                                                   | 2                                                                | 3                                              |
| Gait                                                                                                                                                                                                                                                                                                                                                                                                      | Normal                                                              | Abnormal                                            | but                                                              |                                                |
| walks without  assistance                                                                                                                                                                                                                                                                                                                                                                                 | Abnormal and  requires assistance  (companion, cane,  walker, etc.) | Unable to walk                                      |                                                                  |                                                |
| Key Considerations: 1. Walking is ideally assessed by at least 10 steps.                                                                                                                                                                                                                                                                                                                                  |                                                                     |                                                     |                                                                  |                                                |
| Strength                                                                                                                                                                                                                                                                                                                                                                                                  | Normal                                                              | Movement present  but decreased  against resistance | Movement present  but none against  resistance                   | No movement                                    |
| Key Considerations: 1. Each limb should be tested separately. 2. Recommend  assess proximal (above knee or elbow) and distal (below knee or elbow) major  muscle groups. 3. Score should reflect worst performing area. 4. Patients with  pre-existing level 3 function in one major muscle group/limb at baseline can be  scored based on assessment of other major muscle groups/limb.                  |                                                                     |                                                     |                                                                  |                                                |
| Sensation                                                                                                                                                                                                                                                                                                                                                                                                 | Normal                                                              | Decreased but  aware of sensory  modality           | Unaware of                                                       | ---------                                      |
| sensory modality                                                                                                                                                                                                                                                                                                                                                                                          |                                                                     |                                                     |                                                                  |                                                |
| Key Considerations: 1. Recommend evaluating major body areas separately (face,  limbs and trunk). 2. Score should reflect worst performing area. 3. Sensory  modality includes but not limited to light touch, pinprick, temperature and  proprioception. 4. Patients with pre-existing level 2 function in one major body  area at baseline can be scored based on assessment of other major body areas. |                                                                     |                                                     |                                                                  |                                                |
| Vision                                                                                                                                                                                                                                                                                                                                                                                                    | Normal                                                              | Partial monocular                                   | Complete                                                         |                                                |
| visual loss                                                                                                                                                                                                                                                                                                                                                                                               | monocular visual  loss                                              | Bilateral visual  loss                              |                                                                  |                                                |
| Key Considerations: 1. Patients who require corrective lenses should be  evaluated while wearing corrective lenses. 2. Each eye should be evaluated and  score should reflect worst performing eye.                                                                                                                                                                                                       |                                                                     |                                                     |                                                                  |                                                |
| Eye movements                                                                                                                                                                                                                                                                                                                                                                                             | Normal                                                              | Abnormality  noted in 1 direction of gaze           | Abnormality  noted in more  than 1 gaze  direction, but not  all | Unable to move  the eye in any  gaze direction |
| Key Considerations: 1. Test eye movements for each eye individually. 2. The  score will reflect the worst performing eye (i.e. the highestscore.                                                                                                                                                                                                                                                          |                                                                     |                                                     |                                                                  |                                                |
appendix f linear analog self
appendix g nano (neurologic assessment

Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD  
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)  
| Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB) Level of Function Score Domain 0 1 2 3 Facial Strength Normal Mild facial  weakness  (nasolabial fold  flattening,  asymmetric smile,  decreased forehead  contraction or  partial eye closure) Severe facial  weakness (severe  NLF flattening,  asymmetric smile  with limited or no  movement of face,  incomplete eye  closure, or labial  incompetence Bilateral facial  weakness Key Considerations: 1. Weakness includes nasolabial fold flattening,  asymmetric smile and difficulty elevating eyebrow. Hearing Normal Impaired but  residual  serviceable  hearing Absent unilateral  Bilateral hearing  hearing loss Key Considerations: 1. Each ear should be evaluated and score should reflect  worst performing ear. Swallowing Normal Impaired but not  requiring change  in diet  formulation, not  aspirating by  bedside testing Unable to swallow  without risk of  aspiration by  bedside testing ----------- Key Considerations: 1. Bedside testing comprised of a swallow test with a small  glass of water. Level of Normal Drowsy (easily  Consciousness arousable &  responsive) Somnolent  (difficult to arouse & poorly  responsive) Coma  (unarousable &  unresponsive) Key Considerations: N/A Behavior Normal Mild/moderate  Severe alteration --------- alteration Key Considerations: 1. Alteration includes but is not limited to apathy,  disinhibition and confusion. 2. Consider subclinical seizures forsignificant  alteration. Other* Normal Occasional or  Persistent,  mild moderate to  severe ------------ *Other neurological findings not otherwise defined in the current examination for example ataxia.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD  
  
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)
appendix f linear analog self
appendix h study drug diary

You will use this diary to record each dose of tucatinib and capecitabine that you take. You should also use this diary to record any side effects that you experience and medications that you take other than the study drugs. Please be sure to bring this diary with you to your next clinic visit.  
Tucatinib: Tucatinib is taken twice a day, every day. Capecitabine: Capecitabine is taken twice a day for 14 days, followed by 7 days of no drug (or rest). The study team will tell you if you will also take capecitabine.  
- Please take both tucatinib and capecitabine at about the same times twice each day (usually morning and evening).  
- If you forget to take a dose of either study drug, you should skip that dose and take the next dose at the next regular time.  
- If you vomit after taking a dose of study drug, you should not make up the dose or take additional pills, you should take the next dose at the next regular time. Please, do not retake the pills.  
- Always bring your tucatinib pill bottles (including those that are empty) and your diary with you to each clinic visit.
If you have any questions, please ask a study team member or your doctor.  
| Subject Number:  Subject Initials:  Cycle Number:   | Staff initials   | Date reviewed   |
|-----------------------------------------------------|------------------|-----------------|
| Start Date:                                         |                  |                 |  
Tucatinib dose/number of pills to take at each dose: Capecitabine dose/number of pills to take at each dose: Other information/Comments:
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD  
  
Subject Number/Initials:_________________ Cycle:______________ Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)  
| Tucatinib                     | Capecitabine   | Comments   |            |                            |
|-------------------------------|----------------|------------|------------|----------------------------|
| Cycle Day                     | Due Date       | Date Taken | Time Taken | (Side effects, complaints, |
| # of pills taken at each dose | medications)   |            |            |                            |
| 1                             |                | AM PM      |            |                            |
| 2                             |                | AM PM      |            |                            |
| 3                             |                | AM PM      |            |                            |
| 4                             |                | AM PM      |            |                            |
| 5                             |                | AM PM      |            |                            |
| 6                             |                | AM PM      |            |                            |
| 7                             |                | AM PM      |            |                            |
| 8                             |                | AM PM      |            |                            |
| 9                             |                | AM PM      |            |                            |
| 10                            |                | AM PM      |            |                            |
| 11                            |                | AM PM      |            |                            |
| 12                            |                | AM PM      |            |                            |
| 13                            |                | AM PM      |            |                            |
| 14                            |                | AM PM      |            |                            |
| Continued on Next Page        |                |            |            |                            |  
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)
Subject Number/Initials:_________________ Cycle:______________  
| Tucatinib                     | Capecitabine   | Comments   |                 |                            |
|-------------------------------|----------------|------------|-----------------|----------------------------|
| Cycle Day                     | Due Date       | Date Taken | Time Taken      | (Side effects, complaints, |
| # of pills taken at each dose | medications)   |            |                 |                            |
| 15                            |                | AM         | NO CAPECITABINE |                            |
| PM                            |                |            |                 |                            |
| 16                            |                | AM         | NO CAPECITABINE |                            |
| PM                            |                |            |                 |                            |
| 17                            |                | AM         | NO CAPECITABINE |                            |
| PM                            |                |            |                 |                            |
| 18                            |                | AM         | NO CAPECITABINE |                            |
| PM                            |                |            |                 |                            |
| 19                            |                | AM         | NO CAPECITABINE |                            |
| PM                            |                |            |                 |                            |
| 20                            |                | AM         | NO CAPECITABINE |                            |
| PM                            |                |            |                 |                            |
| 21                            |                | AM         | NO CAPECITABINE |                            |
| PM                            |                |            |                 |                            |  
Comments:
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD  
  
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)
appendix f linear analog self
appendix i recist criteria v

RECIST V1.1 isto be used to assess all extra-CNS sites of disease. Selected sectionsfrom RECIST
V1.1 criteria are below; for detailed guidelines, see the published guideline. 64
appendix f linear analog self
measurability of tumor lesions at

At baseline, tumor lesions will be categorized as follows: measurable (lesions that can be accurately measured in at least one dimension [longest diameter to be recorded] with a minimum size of 10mm with spiral CT scan with slice thickness no greater than 5 mm or if CT scan with slice thickness >5 mm, the minimum lesion size must have a longest diameter twice the actual slice thickness or nonmeasurable (all other lesions, including small lesions [longest diameter < 10 mm with spiral CT scan] and truly nonmeasurable lesions).  
All measurements should be recorded in metric notation by use of a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and nevermore than 4 weeks (approximately 30 days) before the beginning of treatment.  
Lesions considered to be truly nonmeasurable include the following: blastic bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging techniques. Lytic bone lesions and cystic lesions must meet criteria detailed in RECIST 1.1.
appendix f linear analog self
specifications by methods of measurements

The same method of assessment and the same technique should be used to characterizeeach identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the anti-tumor effect of a treatment. Clinical Examination - Clinically detected lesions will be considered measurable only when they are superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, documentation by color photography—including a ruler to estimate the size of the lesion—is required. Chest X-ray - Lesions on chest X-rays may be considered measurable lesions when they are clearly defined and surrounded by aerated lung. CT and MRI - CT and MRI are the best currently available and most reproducible methods for measuring target lesions selected for response assessment. Conventional CT and MRI should be performed with contiguous cuts of 10 mm or less in slice thickness. Spiral CT should be performed by use of a 5-mm or less contiguous reconstruction algorithm; this specification applies to the tumors of the chest, abdomen, and pelvis, whereas head and neck tumors and those of the extremities usually require specific protocols. Ultrasound –It may be used as a possible alternative to clinical measurements for superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules. Ultrasound might also be useful to confirm the complete disappearance of superficial lesions usually assessed by clinicalexamination.  
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD  
  
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)
appendix f linear analog self
tumor response evaluation baseline evaluation

Assessment of Overall Tumor Burden and Measurable Disease - To assess objective response, it is necessary to estimate the overall tumor burden at baseline to which subsequent measurements will be compared. Measurable disease is defined by the presence of at least one measurable lesion, but measurable disease is not required for this protocol. Baseline Documentation of "Target" and "Nontarget" Lesions - All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, may be identified as target lesions and recorded and measured at baseline (this means in instanceswhere patients have only one or two organ sites involved a maximum of two and four lesionsrespectively will be recorded). Target lesions should be selected on the basis of their size (those with thelongest diameter)
and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum of diameters. The baseline sumof diameters will be used as the reference by which to characterize the objective tumor response.All other lesions (or sites of disease) should be identified as non-target lesions and should be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of eachshould be noted throughout followup.
appendix f linear analog self
equivocal new lesions

If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitelya new lesion, then progression should be declared using the date of the initial scan.
appendix f linear analog self
pseudoprogression or equivocal progression

For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of progression should be the earlier date when progression was suspected.
appendix f linear analog self
response criteria

Evaluation of Target Lesions - This section provides the definitions of the criteria used to determine objective tumor response for target lesions. The criteria have been adapted from the original WHO
Handbook, taking into account the measurement of the longest diameter only for all targetlesions: CR— the disappearance of all target lesions; PR—at least a 30% decrease in the sum of thediameters of target lesions, taking as reference the baseline sum of diameters; PD—at least a 20% increase in the sum of the of diameters of target lesions, taking as reference the smallest sum of diameter recorded since the treatment started or the appearance of one or more new lesions; SD—neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as referencethe smallest sum of diameter since the treatmentstarted. Evaluation of Non-target Lesions - This section provides the definitions of the criteria used to determine the objective tumor response for nontarget lesions: CR—the disappearance of all non- target lesions and normalization of tumor marker level; incomplete response/SD—the persistence of one or more nontarget lesion(s) and/or the maintenance of tumor marker level above the normal limits; and PD—the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.  
Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)
REFERENCES
1. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation of relapse  
  
and survival with amplification of the HER-2/neu oncogene. Science 235:177-82, 1987 2. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-92, 2001 3. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-84, 2005 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-72, 2005 5. Slamon D, Eiermann W, Robert N, et al: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273-83, 2011 6. Viani GA, Afonso SL, Stefano EJ, et al: Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 7:153, 2007 7. Blackwell KL, Burstein HJ, Storniolo AM, et al: Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol 28:1124-30, 2010 8. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2positive advanced breast cancer. N Engl J Med 355:2733-43, 2006 9. Johnston S, Pippen J, Jr., Pivot X, et al: Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27:5538-46, 2009 10. Baselga J, Cortes J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-19, 2012 11. Swain SM, Kim SB, Cortes J, et al: Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461-71, 2013 12. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-91, 2012 13. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 32:2078-99, 2014 14. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Breast Cancer. Version 1.2018.  
15. Nahta R, Yu D, Hung MC, et al: Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 3:269-80, 2006 16. Lu Y, Zi X, Zhao Y, et al: Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93:1852-7, 2001 17. Saez R, Molina MA, Ramsey EE, et al: p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin Cancer Res 12:424-31, 2006 18. Pohlmann PR, Mayer IA, Mernaugh R: Resistance to Trastuzumab in Breast Cancer. Clin Cancer Res 15:7479-7491, 2009 Tucatinib and Trastuzumab with Capecitabine for HER2+ LMD
Protocol Chairs: Rashmi Murthy, MD, Barbara O'Brien, MD (MDACC), and Erica Stringer-Reasor, MD (UAB)
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