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dosing guidelines for > grade

Everolimus will be discontinued for all grade 4 hematologic and non-hematologic toxicities. Patients with reactivated Hepatitis B or C will have everolimus treatment discontinued and will be taken off study. Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or PgP inhibitors should be used with caution. If a patient requires co-administration of moderate CYP3A4 inhibitors or PgP inhibitors, reduce the dose of everolimus as specified in Section 6.0. If the inhibitor is discontinued, the Everolimus dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor after a washout period of 2 to 3 days.  
| AST or ALT elevation Grade 3   | Interrupt Everolimus administration until resolution to ≤ grade 1  (or ≤ grade 2 if baseline values were within the range of grade  2). If resolution occurs ≤ 7 days, Everolimusshould be restarted at the dose level prior to interruption. If resolution takes > 7 days, or if event recurs within 28 days,  hold Everolimus until recovery to ≤ grade 1 or baseline grade /  value and reintroduce Everolimus at one dose level lower, if  available.   |
|--------------------------------|---|  
| Intolerable grade 2 mucositis, or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Interrupt Everolimus administration until resolution to ≤ grade 1                                                |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|
| grade 3 AE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | or baseline grade / value. If resolution occurs within ≤ 7 days, Everolimus should be restarted at the dose level prior to interruption. If resolution takes > 7 days, or if event recurs within 28 days,  hold Everolimus until recovery to ≤ grade 1 or baseline grade /  value and reintroduce Everolimus at one dose level lower, if  available. Drug will be discontinued if patients fail to recover to  grade 1  or baseline grade / value within 28 days.                                                                                                                  |
| Recurrence of intolerable grade 2  mucositis or grade 3 event after  dose reduction                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Reduce dose to the next lower dose level, if available. If toxicity  recurs at Grade 3, consider discontinuation |
| Grade 3 clinical liver failure                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Discontinue Everolimus                                                                                           |
| (asterixis or encephalopathy/coma) Any non-hematologic toxicity  requiring Everolimus interruption  for > 28 days                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Discontinue Everolimus                                                                                           |
| Dosing guidelines for Grade 3 Everolimus-related hematologic toxicities Grade 3 thrombocytopenia Interrupt Everolimus until resolution to grade 1  If resolution occurs ≤ 7 days, reintroduce Everolimus at the  dose level prior to interruption. If resolution occurs > 7 days,  or event occurs within 28 days, reintroduce Everolimus at one  dose level lower, if available. Grade 3 neutropenia or anemia Interrupt Everolimus until resolution to grade ≤1 or baseline  value. If AE resolution occurs ≤ 7 days, reintroduce  Everolimus at the same dose level. If AE resolution occurs >  7 days, or event occurs within 28 days, reintroduce  Everolimus at one dose level lower, if available. Grade 4 neutropenia or anemia Interrupt Everolimus until recovery to grade  1 or baseline  value. Reintroduce Everolimus at one dose level lower, if  available* Febrile neutropenia Interrupt Everolimus until resolution to grade  1 (or baseline  value) and no fever. Reintroduce Everolimus at one dose  level lower, if available* Recurrence of grade 3 toxicity after  Reduce dose to the next lower dose level, if available. dose reduction Any hematologic toxicity requiring  Discontinue Everolimus Everolimus interruption for > 28 days |                                                                                                                  |  
Patients with a clinical history of stomatitis/mucositis/mouth ulcers and those with gastrointestinal morbidity associated with mouth/dental infections, irritation of esophageal mucosa such as gastroesophageal reflux disease (GERD) and pre-existing stomatitis/mucositis must be monitored even more closely. Patients should be instructed to report the first onset of buccal mucosa irritation/reddening to their study physician immediately.  
| Management of stomatitis/oral mucositis/mouth ulcers                                                                                                 |                                                                                                                                                                                                                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1 (Minimal                                                                                                                                     | Manage with non-alcoholic or salt water (0.9%) mouth wash several times a                                                                                                                                                                                                                                            |
| symptoms, normal diet)                                                                                                                               | day.                                                                                                                                                                                                                                                                                                                 |
| Grade 2 (Symptomatic  but can eat and swallow  modified diet)                                                                                        | Temporary dose interruption until recovery to grade ≤1. Manage with topical  analgesic mouth treatments (e.g., benzocaine, butyl aminobenzoate, tetracaine  hydrochloride, menthol or phenol) with or without topical corticosteroids (i.e., triamcinolone oral paste 0.1%)*. Re-initiate everolimus at the same dose. If  stomatitis recurs at grade 2, interrupt dose until recovery to grade ≤1. Reinitiate everolimus at a lower dose.                                                                                                                                                                                                                                                                                                                      |
| Grade 3 (Symptomatic  and unable to adequately  eat or hydrate orally)                                                                               | Temporary dose interruption until recovery to grade ≤1. Manage with  topical analgesic mouth treatments (i.e., benzocaine, butyl aminobenzoate,  tetracaine hydrochloride, menthol or phenol) with or without topical  corticosteroids (i.e., triamcinolone oral paste 0.1%)* Re-initiate everolimus  at lower dose. |
| *Do not use agents containing alcohol, hydrogen peroxide, iodine, or thyme derivatives in management of  stomatitis as they may worsen mouth ulcers. |                                                                                                                                                                                                                                                                                                                      |  
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious pneumonitis (including interstitial lung disease) have also been described in patients taking Everolimus.  
| Management of non-infectious pneumonitis                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst grade                                                                                                                                                                                                                                                                       | Suggested investigations                                                                                                                                                                                                                                                                                                          | Management of pneumonitis                                                                                                                                                                                                                                                                                                                    |
| Grade 1                                                                                                                                                                                                                                                                           | CT scans with lung windows.                                                                                                                                                                                                                                                                                                       | No specific therapy is required; initiate  appropriate monitoring                                                                                                                                                                                                                                                                            |
| Grade 2                                                                                                                                                                                                                                                                           | CT scan with lung windows.                                                                                                                                                                                                                                                                                                        | Consider                                                                                                                                                                                                                                                                                                                                     |
| pulmonary function testing includes:  spirometry, DLCO, and room air O2 saturation  at rest. Consider a bronchoscopy with biopsy  and/or BAL. Monitoring at each visit until  return to ≤ grade 1. Return to initial monitoring  frequency if no recurrence.                      | Symptomatic only.                                                                                                                                                                                                                                                                                                                 | Consider corticosteroids                                                                                                                                                                                                                                                                                                                     |
| and/or other supportive therapy if symptoms  are troublesome. Rule out infection and  consider interruption of Everolimus until  symptoms improve to Grade ≤ 1. Re-initiate  Everolimus at one dose level lower.  Discontinue Everolimus if failure to recover  within ≤ 28 days. |                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                              |
| Grade 3                                                                                                                                                                                                                                                                           | CT scan with lung windows and pulmonary  function testing includes: spirometry, DLCO,  and room air O2 saturation at rest. Monitoring  at each visit until return to ≤ grade 1. Return to  initial monitoring frequency if no recurrence.  Bronchoscopy with biopsy and/or BAL is  recommended.                                   | Consider corticosteroids if infective origin is  ruled out. Taper as medically indicated.  Interrupt Everolimus until symptoms improve  to Grade ≤ 1. Consider re-initiating  Everolimus at one dose level lower.  Discontinue Everolimus if failure to recover  within ≤ 28 days. If toxicity recurs at Grade 3,  consider discontinuation. |
| Grade 4                                                                                                                                                                                                                                                                           | CT scan with lung windows and required  pulmonary function testing, if possible,  includes: spirometry, DLCO, and room air O2 saturation at rest. Monitoring at each visit until  return to ≤ grade 1. Return to initial monitoring  frequency if no recurrence. Bronchoscopy with  biopsy and/or BAL is recommended if possible. | Consider corticosteroids if infective origin is  ruled out. Taper as medically indicated.  Discontinue everolimus.                                                                                                                                                                                                                           |  
Note: Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment).
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6.4 agent-specific dose modifications veliparib

If a patient taking Veliparib in combination with temozolomide develops bone marrow findings consistent with AML/MDS or severe persistent anemia, he or she may be allowed to continue the other therapy if they are experiencing clinical benefit and the toxicity is not related to the other therapy, based on the opinion of the Principal Investigator. Hematologic toxicities should have resolved to ≤ Grade 2 (except lymphopenia) prior to starting the next cycle. Doses of study drugs will not be held or reduced for any grade of lymphopenia. Treatment may be delayed for toxicity a maximum of 2 weeks beyond the actual cycle length per Section 6.1.
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use of hematopoietic agents

Use erythropoietin-stimulating agents per standard of care National Comprehensive Cancer Network (NCCN) and/or institutional guidelines, iron supplements, and/or transfusions as clinically indicated for management of anemia. Prescribing information for the erythropoiesis stimulating agents (including Aranesp, Epogen and Procrit) highlight that there is a potential risk of shortening the time to tumor progression or disease-free survival. Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not recommended. Aranesp, Epogen and Procrit may not alleviate fatigue or increase energy and should not be used in patients with uncontrolled hypertension. The package inserts for these agents should be consulted. If a patient develops febrile neutropenia, Veliparib should be stopped and appropriate management including G-CSF should be given according to local hospital guidelines. Please note that G-CSF should not be used within at least 24 hours of the last dose of veliparib unless absolutely necessary. Platelet transfusions, if indicated, should be done according to local hospital guidelines.
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dose modifications for hematologic toxicity

Patients who have veliparib held for hematologic toxicities should have blood counts and differentials checked at least weekly until recovery; these data should be recorded in eCRF as extra laboratory examinations. If counts do not improve to CTCAE Grade 2 or better despite drug cessation for 2 weeks, patients should be referred to a hematological oncologist for further assessment. A bone marrow analysis should be considered.
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management of anemia

Anemia is a common adverse drug reaction related to Veliparib; management of anemia is in accordance with the table below:  
| CTCAE   | Definition   | Dose                                                                                                                                                                                                  |
|---------|--------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 3 | Hb <8 g/dL   | Give appropriate supportive treatment and investigate causality.  Interrupt veliparib until improved to ≥ Grade 2 or baseline. Upon  recovery, therapy will be re-initiated at the same dose level.51 |  
| CTCAE                              | Definition   | Dose                                                                                                                                                                               |
|------------------------------------|--------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 4                            | Hb <8 g/dL   | Give appropriate supportive treatment and investigate causality.  Interrupt veliparib until improved to ≥ Grade 2 or baseline. Upon  recovery, dose reduce veliparib to 20 mg BID. |
| BID = twice daily; Hb = hemoglobin |              |                                                                                                                                                                                    |  
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and hypothyroidism) should be investigated and appropriately managed. In some cases, management of anemia may require blood transfusions. Any subsequently required dose interruptions related to development of anemia, or coexistent with newly developed neutropenia, and/or thrombocytopenia, will require veliparib dose reductions to 20 mg twice daily (BID). If Hb drops to <8 g/dL despite the dose reduction or more than one blood transfusion is required to recover Hb levels with no alternative explanation for the anemia, veliparib should be permanently discontinued.
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management of prolonged hematological toxicities

If a patient develops prolonged hematological toxicity such as:
- ≥2-week interruption/delay in veliparib due to CTCAE Grade ≥3 anemia (Hb <8 g/dL) and/or development of blood transfusion dependence
- ≥2-week interruption/delay in veliparib due to CTCAE Grade ≥3 neutropenia (ANC <1 x 109/L)  
- ≥2-week interruption/delay in veliparib due to CTCAE Grade ≥3 thrombocytopenia and/or development of platelet transfusion dependence (Platelets <50 x 109/L)
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If any blood parameters remain clinically abnormal after 2 weeks of dose interruption, the patient should be referred to a hematological oncologist for further investigations. Bone marrow for evaluation and cytogenetics should be considered at this stage according to standard hematological oncology practice. Patients who develop MDS/AML on treatment should discontinue veliparib treatment and be managed appropriately.
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7. adverse events list and

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited (via CTEP-AERS) **in addition** to routine reporting.
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7.1 comprehensive adverse events and

Please refer to Sections 8.1 and 8.2 for adverse events related to carboplatin and temozolomide.
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7.1.2 caepr for veliparib (nsc

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. *Frequency is provided based on 2310 patients.* Below is the CAEPR for ABT-888 (Veliparib). NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
| Version 2.4, May 13, 2018                                      |                                                              |                                    |
|----------------------------------------------------------------|--------------------------------------------------------------|------------------------------------|
| Adverse Events with Possible                                   |                                                              |                                    |
| Relationship to ABT-888 (Veliparib) (CTCAE 5.0 Term) [n= 2310] | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |                                    |
| Likely (>20%)                                                  | Less Likely (<=20%)                                          | Rare but Serious (<3%)             |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                    | Anemia (Gr 3)                                                |                                    |
| Febrile neutropenia                                            | Febrile neutropenia (Gr 3)                                   |                                    |
| GASTROINTESTINAL DISORDERS Abdominal pain Constipation         | Constipation (Gr 2)                                          |                                    |
| Diarrhea                                                       | Diarrhea (Gr 3)                                              |                                    |
| Nausea                                                         | Nausea (Gr 3)                                                |                                    |
| Vomiting                                                       | Vomiting (Gr 3)                                              |                                    |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue   | Fatigue (Gr 3)                                               |                                    |
| INVESTIGATIONS                                                 | Lymphocyte count decreased                                   | Lymphocyte count decreased  (Gr 4) |
| Neutrophil count decreased                                     | Neutrophil count decreased (Gr 4)                            |                                    |
| Platelet count decreased                                       | Platelet count decreased (Gr 4)                              |                                    |
| Weight loss                                                    | Weight loss (Gr 2)                                           |                                    |
| White blood cell decreased                                     | White blood cell decreased (Gr 4)                            |                                    |  
| Adverse Events with Possible                                                                                                                                                                                                                                                                                                                                                          |                                                              |                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|------------------------|
| Relationship to ABT-888 (Veliparib) (CTCAE 5.0 Term) [n= 2310]                                                                                                                                                                                                                                                                                                                        | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |                        |
| Likely (>20%)                                                                                                                                                                                                                                                                                                                                                                         | Less Likely (<=20%)                                          | Rare but Serious (<3%) |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                                                                                                                                                                                                                                                                           | Anorexia (Gr 2)                                              |                        |
| Dehydration                                                                                                                                                                                                                                                                                                                                                                           | Dehydration (Gr 3)                                           |                        |
| Hypophosphatemia                                                                                                                                                                                                                                                                                                                                                                      | Hypophosphatemia (Gr 3)                                      |                        |
| NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND  POLYPS) Leukemia secondary to  oncology chemotherapy Myelodysplastic syndrome Treatment related secondary  malignancy NERVOUS SYSTEM DISORDERS Dizziness Dysgeusia Dysgeusia (Gr 2) Headache Headache (Gr 3) Seizure SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash maculo-papular VASCULAR DISORDERS Thromboembolic event2 |                                                              |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Thromboembolic events, including deep vein thrombosis and pulmonary embolism, have been observed at a higher frequency compared to control arm when administered in combination with temozolomide.  
Adverse events reported on ABT-888 (Veliparib) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that ABT-888 (Veliparib) caused the adverse event: BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Blood and lymphatic system disorders - Other (pancytopenia) CARDIAC DISORDERS - Cardiac disorders - Other (Takotsubo cardiomyopathy); Heart failure; Left ventricular systolic dysfunction; Palpitations; Sinus bradycardia; Sinus tachycardia EAR AND LABYRINTH DISORDERS - Vertigo EYE DISORDERS - Blurred vision GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Colonic obstruction; Dental caries; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux disease; Lower gastrointestinal hemorrhage; Mucositis oral; Obstruction gastric; Rectal hemorrhage; Rectal pain; Small intestinal obstruction GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema limbs; Fever; Flu like symptoms; Malaise; Non-cardiac chest pain; Pain HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cirrhosis)
INFECTIONS AND INFESTATIONS - Appendicitis; Catheter related infection; Infections and infestations - Other (peritonsillar abscess); Lung infection; Lymph gland infection; Mucosal infection; Sepsis; Shingles; Skin infection; Upper respiratory infection; Urinary tract infection INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Radiation recall reaction (dermatologic)
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin increased; Cardiac troponin I increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; Lipase increased METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hypernatremia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Arthritis; Back pain; Bone pain; Generalized muscle weakness; Muscle cramp; Myalgia; Neck pain; Pain in extremity NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; Dysarthria; Extrapyramidal disorder; Intracranial hemorrhage; Lethargy; Memory impairment; Movements involuntary; Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; Reversible posterior leukoencephalopathy syndrome; Stroke; Syncope; Tremor PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Psychiatric disorders - Other (emotional instability); Psychosis; Restlessness RENAL AND URINARY DISORDERS - Dysuria; Hematuria; Proteinuria RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Respiratory failure SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail changes; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Purpura; Rash acneiform VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Vascular disorders - Other (brainstem infarction)
Note: Veliparib (ABT-888) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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7.1.3 caepr for azd1775 (nsc

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. *Frequency is provided based on 299 patients.* Below is the CAEPR for AZD1775
(MK-1775, NSC 751084). NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. NOTE: Many adverse events on this CAEPR are treatment-emergent events that have been observed in trials of AZD1775 in combination with chemotherapy including carboplatin, cisplatin,  
| with monotherapy of AZD1775 at this time.                                                                            | Version 2.4, August 3, 2016                                   |                          |
|----------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|--------------------------|
| Adverse Events with Possible  Relationship to AZD1775  (CTCAE 4.0 Term) [n= 299]                                     | Specific Protocol Exceptions  to Expedited Reporting  (SPEER) |                          |
| Likely (>20%)                                                                                                        | Less Likely (<=20%)                                           | Rare but Serious (<3%)   |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                                                                          | Anemia (Gr 3)                                                 |                          |
| Febrile neutropenia                                                                                                  |                                                               |                          |
| CARDIAC DISORDERS                                                                                                    | Atrial fibrillation Supraventricular tachycardia              |                          |
| EAR AND LABYRINTH DISORDERS Hearing impaired Tinnitus GASTROINTESTINAL DISORDERS Abdominal distension Abdominal pain | Abdominal pain (Gr 2)                                         |                          |
| Constipation                                                                                                         | Constipation (Gr 2)                                           |                          |
| Diarrhea                                                                                                             | Diarrhea (Gr 2)                                               |                          |
| Dyspepsia Flatulence Mucositis oral                                                                                  | Mucositis oral (Gr 2)                                         |                          |
| Nausea                                                                                                               | Nausea (Gr 2)                                                 |                          |
| Oral pain                                                                                                            |                                                               |                          |
| Vomiting                                                                                                             | Vomiting (Gr 2)                                               |                          |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills Edema limbs                                              | Edema limbs (Gr 2)                                            |                          |
| Fatigue                                                                                                              | Fatigue (Gr 3)                                                |                          |
| Fever                                                                                                                | Fever (Gr 2)                                                  |                          |
| Flu like symptoms Malaise Non-cardiac chest pain Pain                                                                |                                                               |                          |
| HEPATOBILIARY DISORDERS                                                                                              | Hepatobiliary disorders - Other (hepatitis)                   |                          |
| IMMUNE SYSTEM DISORDERS Allergic reaction INFECTIONS AND INFESTATIONS Infection(2)                                   | Infection[81](Gr 3)                                           |                          |
| INVESTIGATIONS                                                                                                       | Alanine aminotransferase                                      | Alanine aminotransferase |
| increased                                                                                                            | increased (Gr 2)                                              |                          |
| Alkaline phosphatase  increased Aspartate aminotransferase  increased                                                | 56                                                            |                          |  
| Adverse Events with Possible  Relationship to AZD1775  (CTCAE 4.0 Term) [n= 299]                                                          | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)   |                        |
|-------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|------------------------|
| Likely (>20%)                                                                                                                             | Less Likely (<=20%)                                             | Rare but Serious (<3%) |
| Blood bilirubin increased Creatinine increased Lymphocyte count decreased                                                                 |                                                                 |                        |
| Neutrophil count decreased                                                                                                                | Neutrophil count decreased (Gr  4)                              |                        |
| Platelet count decreased                                                                                                                  | Platelet count decreased (Gr 4)                                 |                        |
| Weight loss White blood cell decreased                                                                                                    | White blood cell decreased (Gr  4)                              |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                               | Anorexia (Gr 2)                                                 |                        |
| Dehydration Hyperglycemia Hypoalbuminemia Hypocalcemia Hypokalemia                                                                        | Hypokalemia (Gr 2)                                              |                        |
| Hypomagnesemia                                                                                                                            | Hypomagnesemia (Gr 2)                                           |                        |
| Hyponatremia Hypophosphatemia                                                                                                             |                                                                 |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Back pain                                                                      | Back pain (Gr 2)                                                |                        |
| Musculoskeletal and  connective tissue disorder - Other (muscle spasms) Myalgia                                                           | Myalgia (Gr 2)                                                  |                        |
| Pain in extremity                                                                                                                         |                                                                 |                        |
| NERVOUS SYSTEM DISORDERS Dizziness                                                                                                        | Dizziness (Gr 2)                                                |                        |
| Dysgeusia Headache                                                                                                                        | Headache (Gr 2)                                                 |                        |
| Intracranial hemorrhage                                                                                                                   |                                                                 |                        |
| Paresthesia                                                                                                                               |                                                                 |                        |
| PSYCHIATRIC DISORDERS Insomnia RENAL AND URINARY DISORDERS Acute kidney injury (3)  RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough | Cough (Gr 2)                                                    |                        |
| Dyspnea                                                                                                                                   | Dyspnea (Gr 2)                                                  |                        |
| Epistaxis Hiccups                                                                                                                         | Hypoxia                                                         |                        |
| Voice alteration                                                                                                                          |                                                                 |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia                                                                                           | 57                                                              |                        |  
| Adverse Events with Possible  Relationship to AZD1775  (CTCAE 4.0 Term) [n= 299]   | Specific Protocol Exceptions  to Expedited Reporting  (SPEER)   |                        |
|------------------------------------------------------------------------------------|-----------------------------------------------------------------|------------------------|
| Likely (>20%)                                                                      | Less Likely (<=20%)                                             | Rare but Serious (<3%) |
| Hyperhidrosis Pruritus Rash (4)                                                    | Rash[82](Gr 2)                                                  |                        |
| VASCULAR DISORDERS                                                                 | Phlebitis                                                       |                        |
| Thromboembolic event                                                               |                                                                 |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 3Acute kidney injury includes renal impairment and acute renal insufficiency.  
4Rash may include rash, erythema, eczema, and rash maculo-papular.  
5Peripheral neuropathy includes both peripheral motor neuropathy and peripheral sensory neuropathy. Adverse events reported on AZD1775 trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that AZD1775 caused the adverse event: BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other (pancytopenia); Blood and lymphatic system disorders - Other (thrombocytosis); Leukocytosis CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (cardiomegaly); Chest pain - cardiac; Myocardial infarction; Palpitations; Sinus bradycardia; Sinus tachycardia EAR AND LABYRINTH DISORDERS - Ear pain EYE DISORDERS - Blurred vision; Cataract; Conjunctivitis; Eye disorders - Other (eye swelling); Eye disorders - Other (visual impairment); Eye pain; Keratitis; Photophobia; Scleral disorder; Watering eyes GASTROINTESTINAL DISORDERS - Anal pain; Ascites; Bloating; Cheilitis; Colitis; Dry mouth; Duodenal ulcer; Dysphagia; Gastric ulcer; Gastritis; Gastrointestinal disorders - Other (duodenitis); Gastrointestinal disorders - Other (eructation); Hemorrhoids; Lower gastrointestinal hemorrhage; Rectal pain; Small intestinal obstruction GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Gait disturbance; General disorders and administration site conditions - Other (catheter site pain); Infusion site extravasation INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural complications - Other (excoriation); Injury, poisoning and procedural complications - Other
(ligament sprain)
INVESTIGATIONS - Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - Other (blood urea increased); Lymphocyte count increased METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hyperkalemia; Hyperuricemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Bone pain; Flank pain; Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other (groin pain); Neck pain NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (carcinoid tumor); Tumor pain NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Dysesthesia; Encephalopathy; Lethargy; Nervous system disorders - Other (hemiparesis); Peripheral neuropathy[83]; Presyncope; Somnolence; Syncope PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression RENAL AND URINARY DISORDERS - Hematuria; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract pain REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Female genital tract fistula; Genital edema RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; Bronchopulmonary hemorrhage; Nasal congestion; Pleural effusion; Pneumonitis; Pulmonary hypertension; Respiratory, thoracic and mediastinal disorders - Other (diaphragmalgia); Wheezing SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Purpura; Rash acneiform; Skin ulceration; Urticaria VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension Note: AZD1775 in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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7.1.4 caepr for trametinib dmso

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI
(except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdffor further clarification. *Frequency is provided based on 1111 patients.* Below is the CAEPR for Trametinib (GSK1120212B).  
NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required.  
Version 2.6, October 10, 20191  
| Version 2.6, October 10, 20191                                      |                                                               |                        |
|---------------------------------------------------------------------|---------------------------------------------------------------|------------------------|
| Adverse Events with Possible                                        |                                                               |                        |
| Relationship to Trametinib (GSK1120212B) (CTCAE 5.0 Term) [n= 1111] | Specific Protocol Exceptions  to Expedited Reporting  (SPEER) |                        |
| Likely (>20%)                                                       | Less Likely (<=20%)                                           | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                         | Anemia (Gr 3)                                                 |                        |
| CARDIAC DISORDERS                                                   | Heart failure Left ventricular systolic  dysfunction          |                        |
| Sinus bradycardia                                                   |                                                               |                        |
| EYE DISORDERS                                                       | Blurred vision Dry eye                                        |                        |  
| Adverse Events with Possible                                                                                                                     |                                                               |                                            |
|--------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|--------------------------------------------|
| Relationship to Trametinib (GSK1120212B) (CTCAE 5.0 Term) [n= 1111]                                                                              | Specific Protocol Exceptions  to Expedited Reporting  (SPEER) |                                            |
| Likely (>20%)                                                                                                                                    | Less Likely (<=20%)                                           | Rare but Serious (<3%)                     |
| Eye disorders - Other  (chorioretinopathy also known as  retinal pigment epithelial  detachment) Eye disorders - Other (retinal vein  occlusion) |                                                               |                                            |
| Eye disorders - Other (visual  disorders)2                                                                                                       | Papilledema                                                   |                                            |
| Periorbital edema                                                                                                                                |                                                               |                                            |
| GASTROINTESTINAL DISORDERS Abdominal pain                                                                                                        | Abdominal pain (Gr 2)                                         |                                            |
| Colitis Colonic perforation                                                                                                                      |                                                               |                                            |
| Constipation                                                                                                                                     | Constipation (Gr 2)                                           |                                            |
| Diarrhea                                                                                                                                         | Diarrhea (Gr 3)                                               |                                            |
| Dry mouth                                                                                                                                        | Dry mouth (Gr 2)                                              |                                            |
| Dyspepsia                                                                                                                                        | Dyspepsia (Gr 2)                                              |                                            |
| Mucositis oral                                                                                                                                   | Mucositis oral (Gr 3)                                         |                                            |
| Nausea                                                                                                                                           | Nausea (Gr 3)                                                 |                                            |
| Vomiting                                                                                                                                         | Vomiting (Gr 3)                                               |                                            |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Chills                                                                                      | Chills (Gr 2)                                                 |                                            |
| Edema face                                                                                                                                       |                                                               |                                            |
| Fatigue                                                                                                                                          | Fatigue (Gr 3)                                                |                                            |
| Fever                                                                                                                                            | Fever (Gr 2)                                                  |                                            |
| Generalized edema3                                                                                                                               | Generalized edema3 (Gr 2)                                     |                                            |
| IMMUNE SYSTEM DISORDERS Allergic reaction4 INFECTIONS AND INFESTATIONS Folliculitis                                                              | Folliculitis (Gr 2)                                           |                                            |
| Lung infection Paronychia                                                                                                                        | Paronychia (Gr 2)                                             |                                            |
| Skin infection                                                                                                                                   | Skin infection (Gr 2)                                         |                                            |
| INVESTIGATIONS                                                                                                                                   | Alanine aminotransferase increased                            | Alanine aminotransferase  increased (Gr 3) |
| Alkaline phosphatase increased                                                                                                                   | Alkaline phosphatase increased  (Gr 2)                        |                                            |
| Aspartate aminotransferase                                                                                                                       | Aspartate aminotransferase                                    |                                            |
| increased                                                                                                                                        | increased (Gr 3)                                              |                                            |
| CPK increased Ejection fraction decreased                                                                                                        |                                                               |                                            |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                                      | Anorexia (Gr 3)                                               |                                            |
| Dehydration                                                                                                                                      | Dehydration (Gr 3)                                            |                                            |
| 60                                                                                                                                               |                                                               |                                            |  
| Adverse Events with Possible                                                                                      |                                                               |                        |
|-------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|------------------------|
| Relationship to Trametinib (GSK1120212B) (CTCAE 5.0 Term) [n= 1111]                                               | Specific Protocol Exceptions  to Expedited Reporting  (SPEER) |                        |
| Likely (>20%)                                                                                                     | Less Likely (<=20%)                                           | Rare but Serious (<3%) |
| Hypoalbuminemia Hypomagnesemia                                                                                    | Hypomagnesemia (Gr 2)                                         |                        |
| Hyponatremia                                                                                                      | Hyponatremia (Gr 3)                                           |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Back pain                                              | Back pain (Gr 2)                                              |                        |
| Pain in extremity                                                                                                 | Pain in extremity (Gr 2)                                      |                        |
| Rhabdomyolysis                                                                                                    |                                                               |                        |
| NERVOUS SYSTEM DISORDERS Dizziness                                                                                | Dizziness (Gr 2)                                              |                        |
| Headache                                                                                                          | Headache (Gr 2)                                               |                        |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough                                                             | Cough (Gr 2)                                                  |                        |
| Dyspnea                                                                                                           | Dyspnea (Gr 3)                                                |                        |
| Pneumonitis                                                                                                       |                                                               |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia                                                                   | Alopecia (Gr 2)                                               |                        |
| Dry skin                                                                                                          | Dry skin (Gr 2)                                               |                        |
| Nail changes                                                                                                      | Palmar-plantar erythrodysesthesia  syndrome                   |                        |
| Pruritus                                                                                                          | Pruritus (Gr 2)                                               |                        |
| Skin and subcutaneous tissue  disorders - Other (drug reaction  with eosinophilia and systemic  symptoms [DRESS]) |                                                               |                        |
| Skin and subcutaneous tissue                                                                                      | Skin and subcutaneous tissue                                  |                        |
| disorders - Other (rash)5                                                                                         | disorders - Other (rash)5 (Gr 3)                              |                        |
| Stevens-Johnson syndrome6                                                                                         |                                                               |                        |
| VASCULAR DISORDERS                                                                                                | Hypertension                                                  | Hypertension (Gr 3)    |
| Thromboembolic event (venous)                                                                                     |                                                               |                        |
| Vascular disorders - Other  (hemorrhage)7                                                                         |                                                               |                        |
| 1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all   |                                                               |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, corneal graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, visual acuity reduced, visual impairment, and vitreous detachment.  
3Generalized edema includes edema, lymphedema, and edema limbs.  
4Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased liver function tests, and visual disturbances.  
5Skin and subcutaneous tissue disorders -Other (rash) may include rash, rosacea, rash acneiform, erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash papular, seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin chapped.  
6Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib combination.  
7The majority of hemorrhage events were mild. Major events, defined as symptomatic bleeding in a critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and fatal intracranial hemorrhages have been reported. Adverse events reported on trametinib dimethyl sulfoxide (GSK1120212B) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that trametinib dimethyl sulfoxide (GSK1120212B) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS -Disseminated intravascular coagulation; Febrile neutropenia; Leukocytosis CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial infarction; Restrictive cardiomyopathy; Sinus tachycardia EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing lights; Floaters; Glaucoma; Photophobia GASTROINTESTINAL DISORDERS -Ascites; Duodenal ulcer; Esophageal necrosis; Esophageal ulcer; Esophagitis; Gastric hemorrhage7; Gastric ulcer; Gastritis; Gastrointestinal disorders -Other (intestinal obstruction); Gastrointestinal disorders -Other (pneumatosis intestinalis); Gastrointestinal fistula; Gingival pain; Hemorrhoidal hemorrhage7; Ileus; Obstruction gastric; Pancreatitis; Small intestinal obstruction GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -Flu like symptoms; General disorders and administration site conditions -Other (axillary pain); Localized edema; Malaise; Non-cardiac chest pain; Pain HEPATOBILIARY DISORDERS -Cholecystitis; Hepatic failure; Hepatic pain; Hepatobiliary disorders -
Other (hepatic encephalopathy) INFECTIONS AND INFESTATIONS -Biliary tract infection; Catheter related infection; Device related infection; Endocarditis infective; Enterocolitis infectious; Hepatitis viral; Infections and infestations -Other (abscess limb); Infections and infestations -Other (necrotizing fasciitis); Infections and infestations -Other (oral infection); Pharyngitis; Sepsis; Upper respiratory infection; Urinary tract infection INJURY, POISONING AND PROCEDURAL COMPLICATIONS -Bruising INVESTIGATIONS -Blood bilirubin increased; Blood lactate dehydrogenase increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; Lipase increased; Lymphocyte count decreased; Platelet count decreased; Serum amylase increased; White blood cell decreased METABOLISM AND NUTRITION DISORDERS -Hyperglycemia; Hyperkalemia; Hyperphosphatemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -Generalized muscle weakness; Muscle cramp; Musculoskeletal and connective tissue disorder -Other (compression fracture); Myalgia; Neck pain NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor hemorrhage7; Tumor pain NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage7; Lethargy; Nervous system disorders -Other (diplopia); Seizure; Somnolence; Stroke; Syncope; Transient ischemic attacks PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; Personality change RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; Dysuria; Hematuria; Proteinuria; Urinary incontinence REPRODUCTIVE SYSTEM AND BREAST DISORDERS -Vaginal fistula; Vaginal hemorrhage7 62 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS -Bronchopulmonary hemorrhage7; Hypoxia; Laryngeal edema; Oropharyngeal pain; Pleural effusion; Pneumothorax; Productive cough; Pulmonary hypertension; Respiratory failure; Sinus disorder SKIN AND SUBCUTANEOUS TISSUE DISORDERS -Bullous dermatitis; Photosensitivity; Purpura; Skin and subcutaneous tissue disorders -Other (erythema nodosum); Skin ulceration; Urticaria VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension Note: Trametinib (GSK1120212B) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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7.1.5 caepr for everolimus (rad-001

The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. *Frequency is provided based on 3033 patients.* Below is the CAEPR for Everolimus (RAD-001).  
NOTE: Report AEs on the SPEER **ONLY IF** they exceed the grade noted in parentheses next to the AE  
in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is  
required.  
Version 2.5, July 3, 2018  
Adverse Events with Possible  
Relationship to Everolimus (RAD-001)  
(CTCAE 5.0 Term)  
[n= 3033]  
| Version 2.5, July 3, 2018                                        |                                                              |                        |
|------------------------------------------------------------------|--------------------------------------------------------------|------------------------|
| Adverse Events with Possible                                     |                                                              |                        |
| Relationship to Everolimus (RAD-001) (CTCAE 5.0 Term) [n= 3033]  | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |                        |
| Likely (>20%)                                                    | Less Likely (<=20%)                                          | Rare but Serious (<3%) |
| BLOOD AND LYMPHATIC SYSTEM DISORDERS Anemia                      | Anemia (Gr 3)                                                |                        |
| GASTROINTESTINAL DISORDERS Abdominal pain Constipation Diarrhea2 | Diarrhea2 (Gr 3)                                             |                        |
| Mucositis oral3                                                  | Mucositis oral3 (Gr 3)                                       |                        |
| Nausea                                                           | Nausea (Gr 3)                                                |                        |
| Vomiting                                                         | Vomiting (Gr 3)                                              |                        |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Edema limbs | Edema limbs (Gr 2)                                           |                        |
| Fatigue                                                          | Fatigue (Gr 3)                                               |                        |
| Fever                                                            | Fever (Gr 2)                                                 |                        |
| IMMUNE SYSTEM DISORDERS                                          | Allergic reaction Anaphylaxis                                |                        |
| INFECTIONS AND INFESTATIONS Infection4                           | Infection4 (Gr 3)                                            |                        |  
| Adverse Events with Possible                                                                                                       |                                                              |                        |
|------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|------------------------|
| Relationship to Everolimus (RAD-001) (CTCAE 5.0 Term) [n= 3033]                                                                    | Specific Protocol Exceptions to  Expedited Reporting (SPEER) |                        |
| Likely (>20%)                                                                                                                      | Less Likely (<=20%)                                          | Rare but Serious (<3%) |
| INJURY, POISONING AND PROCEDURAL COMPLICATIONS Wound complication5 INVESTIGATIONS Alanine aminotransferase                         | Alanine aminotransferase increased                           |                        |
| increased                                                                                                                          | (Gr 2)                                                       |                        |
| Alkaline phosphatase                                                                                                               | Alkaline phosphatase increased (Gr 2)                        |                        |
| increased Aspartate aminotransferase                                                                                               | Aspartate aminotransferase increased                         |                        |
| increased                                                                                                                          | (Gr 2)                                                       |                        |
| Cholesterol high                                                                                                                   | Cholesterol high (Gr 2)                                      |                        |
| Creatinine increased                                                                                                               | Creatinine increased (Gr 2)                                  |                        |
| Lymphocyte count decreased                                                                                                         | Lymphocyte count decreased (Gr 2)                            |                        |
| Neutrophil count decreased                                                                                                         | Neutrophil count decreased (Gr 4)                            |                        |
| Platelet count decreased                                                                                                           | Platelet count decreased (Gr 4)                              |                        |
| Weight loss White blood cell decreased                                                                                             | White blood cell decreased (Gr 4)                            |                        |
| METABOLISM AND NUTRITION DISORDERS Anorexia                                                                                        | Anorexia (Gr 2)                                              |                        |
| Hyperglycemia6                                                                                                                     | Hyperglycemia6 (Gr 3)                                        |                        |
| Hypertriglyceridemia                                                                                                               | Hypertriglyceridemia (Gr 4)                                  |                        |
| Hypophosphatemia                                                                                                                   | Hypophosphatemia (Gr 2)                                      |                        |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia Back pain Pain in extremity NERVOUS SYSTEM DISORDERS Dysgeusia Headache | Headache (Gr 2)                                              |                        |
| RENAL AND URINARY DISORDERS                                                                                                        | Acute kidney injury                                          |                        |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough                                                                              | Cough (Gr 2)                                                 |                        |
| Dyspnea                                                                                                                            | Dyspnea (Gr 3)                                               |                        |
| Epistaxis                                                                                                                          | Epistaxis (Gr 2)                                             |                        |
| Pneumonitis7                                                                                                                       |                                                              |                        |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS Dry skin Pruritus Rash maculo-papular                                                       | Rash maculo-papular (Gr 2)                                   |                        |
| Skin and subcutaneous tissue  disorders - Other  (angioedema)8                                                                     |                                                              |                        |
| 1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all                    |                                                              |                        |  
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included in the e-mail.  
2Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea.  
3Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. 4Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 5Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma.  
6Hyperglycemia may result in either exacerbation of or development of new onset diabetes mellitus.  
7Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, alveolitis, pulmonary fibrosis, and restrictive pulmonary disease.  
8Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema.  
9Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder.  
Adverse events reported on everolimus (RAD-001) trials, but for which there is insufficient evidence to suggest that there was a reasonable possibility that everolimus (RAD-001) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Thrombotic thrombocytopenic purpura CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (myocardial abnormality); Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia ENDOCRINE DISORDERS - Endocrine disorders - Other (increased blood follicle stimulating hormone [FSH] levels); Endocrine disorders - Other (increased blood luteinizing hormone [LH] levels); Hypothyroidism; Testosterone deficiency EYE DISORDERS - Blurred vision; Keratitis GASTROINTESTINAL DISORDERS - Ascites; Colitis; Dry mouth; Dyspepsia; Dysphagia; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (Dieulafoy's lesion); Hemorrhoids; Intra-abdominal hemorrhage; Oral pain; Pancreatitis; Periodontal disease; Toothache GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Edema trunk; Flu like symptoms; Non-cardiac chest pain; Pain HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (hepatomegaly) INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bicarbonate decreased; Blood bilirubin increased; Blood lactate dehydrogenase increased; CPK increased; GGT increased; INR
increased; Investigations - Other (low density lipoprotein raised); Investigations - Other (thrombocythemia).  
METABOLISM AND NUTRITION DISORDERS - Dehydration; Glucose intolerance; Hypercalcemia; Hyperkalemia; Hyperlipidemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Metabolism and nutrition disorders - Other (high ammonia)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; Generalized muscle weakness; Muscle cramp; Muscle weakness lower limb; Myalgia NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) -
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (ovarian cysts)
NERVOUS SYSTEM DISORDERS - Dizziness; Encephalopathy; Hydrocephalus; Lethargy; Paresthesia PSYCHIATRIC DISORDERS - Agitation; Anxiety[76]; Delirium; Depression; Insomnia; Irritability; Mania RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Urinary frequency REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dysmenorrhea; Genital edema; Irregular menstruation; Menorrhagia; Vaginal hemorrhage RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Pharyngolaryngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (rales); Rhinorrhea; Sore throat; Voice alteration SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Nail loss; Palmar-plantar erythrodysesthesia syndrome; Rash acneiform; Skin and subcutaneous tissue disorders - Other (nail disorder); Skin and subcutaneous tissue disorders - Other (skin lesion); Skin ulceration VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; Phlebitis; Thromboembolic event; Vascular disorders - Other (acute bowel ischemia); Vascular disorders - Other (hemorrhage) Note: Everolimus (RAD-001) in combination with other agents could cause an exacerbation of any adverse event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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7.2 adverse event characteristics

- **CTCAE term (AE description) and grade:** The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP Web site (http://ctep.cancer.gov).  
- **'Expectedness'**: AEs can be 'Unexpected' or 'Expected' (see Section 7.1 above) for expedited reporting purposes only. Specific Protocol Exceptions to Expedited Reporting (SPEER) appears as bold *and italicized* text in the CAEPR (Section 7.1).  
- **Attribution** of the AE: Definite - The AE *is clearly related* to the study treatment; Probable - The AE *is likely related* to the study treatment; Possible - The AE may be related to the study treatment; Unlikely - The AE *is doubtfully related* to the study treatment; Unrelated - The AE *is clearly NOT related* to the study treatment.
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7.3 expedited adverse event reporting

7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov). The reporting procedures to be followed are presented in the "CTEP, NCI Guidelines: Adverse Event Reporting Requirements" which can be downloaded from the CTEP home page (http://ctep.cancer.gov). These requirements are briefly outlined in the table below (Section 7.3.2). In the rare event when Internet connectivity is disrupted, a 24-hour notification is to be made to NCI by telephone at: (301) 897-7497. An electronic report MUST be submitted immediately upon re-establishment of internet connection. CTEP-AERS is programmed for automatic electronic distribution of reports to the following individuals: Study Coordinator of the Lead Organization, lead organization study research nurses, Principal Investigator, and the local treating physician. CTEP-AERS provides a copy feature for other e-mail recipients.  
7.3.2 **Phase 1 and Early Phase 2 Studies:** Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational agent/Intervention 1,2  
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
- Death - A life-threatening adverse event - An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours - A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions - A congenital anomaly/birth defect. - Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic submission within the timeframes detailed in the table below.  
| Hospitalization                   | Grade 1 and Grade 2 Timeframes   | Grade 3-5 Timeframes   |
|-----------------------------------|----------------------------------|------------------------|
| Resulting in  Hospitalization     | 10 Calendar Days                 |                        |
| ≥ 24 hrs                          | 24-Hour 5 Calendar Days          |                        |
| Not resulting in  Hospitalization | Not required                     |                        |
| ≥ 24 hrs                          |                                  |                        |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.  
Expedited AE reporting timelines are defined as:
1) "24-Hour; 5 Calendar Days" - The AE must initially be submitted electronically within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
2) "10 Calendar Days" - A complete expedited report on the AE must be submitted electronically within 10 calendar days of learning of the AE.  
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:
Expedited 24-hour notification followed by complete report within 5 calendar days for:
- All Grade 3, 4, and Grade 5 AEs Expedited 10 calendar day reports for:
- Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP
to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this reporting period.  
Effective Date: May 5, 2011 7.3.3 Protocol-specific expedited AE reporting exclusions. Lymphopenia (any grade), alopecia (any grade), anemia (grade 2), electrolytes (grade 2: sodium, potassium, phosphorous, and magnesium), albumin (grade 2), hyperuricemia (grade 3), INR (grade 2), and PTT (grade 2) will NOT be reported through CTEP-AERS but will be reported in the routine data submissions. 7.3.4 Pregnancy, Pregnancy Loss, and Death Neonatal NOTE: When submitting CTEP-AERS reports for "Pregnancy", "Pregnancy loss", or "Neonatal loss", the Pregnancy Information Form should be completed and faxed along with any additional medical information to **301-230-0159.** The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) should be documented in the "Description of Event" section of the CTEP-AERS report.
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7.3.4.1 pregnancy

- Because patients who become pregnant on study risk intrauterine exposure of the fetus to agents which may be teratogenic, DCTD/DCP is requesting that pregnancy should be reported in an expedited manner via CTEP-AERS as Grade 3 "Pregnancy, puerperium and perinatal conditions - *Other (pregnancy*)" under the *Pregnancy, puerperium and perinatal conditions* SOC.  
- The pregnancy outcome for patients on study should be reported via CTEP-AERS
at the time the outcome becomes known, accompanied by the same Pregnancy Report Form used for the initial report
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7.3.4.2 pregnancy loss

- Pregnancy loss is defined in CTCAE as "Death in utero."
- Any pregnancy loss should be reported expeditiously, as Grade 4 "Pregnancy loss" under the Pregnancy, puerperium and perinatal conditions SOC.  
- A pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes this event as a patient death.
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7.3.4.3 death neonatal

- Neonatal death, defined in CTCAE as "A disorder characterized by cessation of life occurring during the first 28 days of life" that is felt by the investigator to be at least possibly due to the investigational agent/intervention, should be reported expeditiously.  
- A neonatal death should be reported expeditiously as Grade 4 "Death neonatal" under the General disorders and administration SOC.  
- Neonatal death should NOT be reported as Grade 5 "Death neonatal" under the General disorders and administration SOC. If reported as such, the CTEP-AERS interprets this as a death of the patient being treated.
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7.4 routine adverse event reporting

All Adverse Events **must** be reported in routine study data submissions. **AEs reported** expeditiously through CTEP-AERS must also be reported in routine study data
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submissions.

Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. AEs are reported in a routine manner at scheduled times during the trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine AE reporting in Rave.
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7.5 secondary malignancy

A *secondary malignancy* is a cancer caused by treatment for a previous malignancy (e.g., treatment with investigational agent/intervention, radiation, or chemotherapy). A secondary malignancy is not considered a metastasis of the initial neoplasm. CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
1. Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 2. Myelodysplastic syndrome (MDS) 3. Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be reported via the routine reporting mechanisms outlined in each protocol.
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7.6 second malignancy

A second malignancy is one unrelated to the treatment of a prior malignancy (and is **NOT** a metastasis from the initial malignancy). Second malignancies require **ONLY** routine reporting via CDUS unless otherwise specified.
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8. pharmaceutical information

A list of the adverse events and potential risks associated with these agents can be found in Section 7.1.
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8.1 temozolomide (nsc 362856)

Availability: Please refer to the FDA-approved package insert for complete product information.  
Commercial supplies of temozolomide will be purchased by the DCTD, NCI and distributed by the Pharmaceutical Management Branch, CTEP. Toxicities: The most common adverse events across the cumulative temozolomide experience were alopecia, nausea, vomiting, anorexia, headache, and constipation. Forty-nine percent (49%) of patients treated with temozolomide reported one or more severe or life-threatening events, most commonly fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). Myelosuppression (neutropenia and thrombocytopenia), which is a known DLT for most cytotoxic agents, was observed, as were Grade 3 or Grade 4 neutrophil abnormalities including neutropenic events, and Grade 3 or Grade 4 platelet abnormalities, including thrombocytopenic events. Chemical Name: 3,4-dihydro-3-11 methyl-4-oxoimidazo(5,1-d)-as-tetrazine-8-carboxamide. Other Names: Temodar®, Temodal, Temcad
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cas registry number 85622-93-1 molecular

Mode of Action: Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound MTIC. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine. How Supplied: PMB, CTEP, DCTD distributes commercially labeled Temozolomide as 5 mg, 20 mg, 100 mg and 250 mg capsules for oral administration. Each bottle contains 5 capsules.  
The dose of temozolomide is to be rounded to the nearest 5 mg. The manufacturer of the NCIpurchased supplies may vary throughout the course of the trial. Temozolomide capsules contain the following inactive ingredients: lactose anhydrous, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, and stearic acid in varying quantities per capsule strength. Refer to the approved package insert for complete product information and physical description of the supplied product. Storage: Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Stability: Refer to the package label for shelf life.
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route of administration oral.

Method of Administration: Take each day's dose of capsules at one time, with a full glass of water. They should be swallowed whole and **never chewed**. If capsules are vomited do not take a second dose. New capsules should not be taken until the next planned dose. The incidence of nausea and vomiting is decreased when temozolomide is taken on an empty stomach.
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8.2 carboplatin (nsc 241240)

Availability: Please refer to the FDA-approved package insert for complete product information.  
Commercial supplies of Carboplatin will be purchased by the DCTD, NCI and distributed by the Pharmaceutical Management Branch, CTEP. How supplied: PMB, CTEP, DCTD distributes commercially-labeled supplies of Carboplatin aqueous solution Injection as 450 mg/45 mL (10 mg/mL in Water for Injection) multi-dose vials. The manufacturer of the NCI-purchased supplies may vary throughout the course of the trial. Refer to the approved package insert for complete product information and description of the supplied product. Preparation: Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP. Storage and Stability: Unopened vials of Carboplatin aqueous solution are stable to the date indicated on the package when stored at 25°C (77°F); excursions permitted from 15°-30°C (59°- 86°F) [see USP Controlled Room Temperature]. Protect from light. Carboplatin aqueous solution multi-dose vials maintain microbial, chemical, and physical stability for up to 14 days at 25°C following initial vial entry. When prepared as directed, carboplatin solutions for infusion are stable for 8 hours at room temperature (25°C). Prepared solutions for infusion are to be discarded 8 hours after preparation. NOTE: Aluminum reacts with carboplatin, causing precipitate formation and loss of potency. Therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin. Dosing and Administration: Carboplatin will be administered concomitantly with AZD1775 as an i.v. infusion over 30-70 minutes. The dose will be calculated based on the patient's actual body weight at each treatment visit and the AUC (area under curve) dosing according to the formula provided below. The calculated GFR for the carboplatin dose will be based on the calculated creatinine clearance using the Cockroff-Gault formula. Calvert Formula for carboplatin dose: AUC Dose = 5.0 x (GFR + 25) Where GFR (Cockroff-Gault): GFR = (140 - pt. age in years) (weight in Kg) x 0.85 (females) or 1.0 (males)
serum creatinine x 72 The GFR (calculated by Cockcroft-Gault or any other means using creatinine) used in the Calvert formula to calculate AUC-based dosing should not exceed 125 **mL/min under any** circumstance. **By definition, this results in the following upper limits on the dose to be** administered, by AUC target:  
| AUC target   | Maximum carboplatin dose   |
|--------------|----------------------------|
| (mg•min/mL)  | (mg)                       |
| 4            | 600                        |
| 5            | 750                        |  
Questions about this calculation should be directed at the study investigator.  
Toxicities: Some of the expected adverse events from carboplatin are listed below. For further description of adverse events,see Package Insert. Hematologic: Myelosuppression Gastrointestinal: Nausea, vomiting, diarrhea, weight loss, constipation, gastrointestinal pain Metabolic: Electrolyte imbalances, hypomagnesemia, hypocalcemia, hyponatremia, hyperuremia, hypokalemia Hepatic:Elevated alkaline phosphatase, AST, and total bilirubin CNS: Peripheral neuropathies (mild paresthesias, clinical ototoxicity and other sensory abnormalities are rare) Genitourinary: Renal tubular damage, renal insufficiency, impotence, sterility, amenorrhea, gynecomastia Allergy: Anaphylactoid and urticarial reactions (acute), flushing, rash, pruritis, and rarely hypotension or bronchospasm Other: Alopecia, pain, asthenia, and mucosal side effects Patient Care Implications: Patients taking carboplatin should avoid the use of live vaccines and close contact with those who have received live vaccines. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
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8.3 everolimus (nsc 733504)

Chemical Name: (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18dihydroxy-12-{(1R)-2-((1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl)-1methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4azatricyclo(30.3.1.04,9)hexatriaconta-16,24, 26,28-tetraene-2,3,10,14,20-pentaone Other Names: RAD001, Afinitor Classification: mTOR inhibitor CAS Registry Number: 159351-69-6 Molecular Formula: C53H83NO14 **M.W.:** 958.2 Mode of Action: Everolimus is an inhibitor of selective mammalian target of rapamycin
(mTOR), the effects of which specifically target the mTOR-raptor signal transduction complex 1 (mTORC1). Inhibition of mTORC1, an essential regulator of global protein synthesis downstream on the PI3K/AKT/mTOR pathway, reduces tumor cell proliferation, glycolysis, and angiogenesis. The PI3K/AKT/mTOR pathway is dysregulated in the majority of human cancers and is the object of many targeted agents. Description: White to faintly yellow powder How Supplied: Novartis supplies and PMB, CTEP, DCTD distributes commercially labeled Everolimus as 2.5 mg, 5 mg, and 10 mg tablets for oral administration. Each box of 28 tablets contains 4 blistercards of 7 tablets each. The white to slightly yellow, elongated tablets are distinguished as follows:
- 2.5 mg tablet is engraved with "LCL" on one site and "NVR" on the other - 5 mg tablet is engraved with "5" on one side and "NVR" on the other
- 10 mg tablet is engraved with "UHE" on one side and "NVR" on the other Tablet excipients include drug substance, 0.2% butylated hydroxytoluene (BHT), magnesium stearate, lactose anhydrous/anhydrous lactose, lactose monohydrate, hypromellose/hydroxypropyl methylcellulose, and crospovidone. Storage: Store at 25°C (77°F) [excursions permitted between 15 to 30°C (59 to 85°F]. Stability: Refer to the package label for shelf life. Store tablets in the original container and protect from light and moisture. Route and Method **of Administration:** Oral administration. Tablets should be swallowed whole with a glass of water. They can be taken with or without food but should be taken consistently the same time every day. If a dose is missed, it can still be taken up to 6 hours after the usual time of administration. Missed doses more than 6 hours late should be skipped for that day. Potential Drug Interactions: Everolimus is a substrate of CYP3A4 and P-glycoprotein (PgP). Concomitant treatment with strong inhibitors or inducers of CYP3A4 or PgP should be avoided. Use caution when everolimus is given concomitantly with moderate inhibitors or inducers of CYP3A4 and PgP. Consult the protocol document or study investigator prior to making any dose adjustments related to potential drug-drug interactions. In vitro, everolimus is a competitive inhibitor of CYP3A4, a mixed inhibitor of CYP2D6, an inhibitor of transport proteins, OATP1B1 and OATP1B3 and a moderate inhibitor of P-gp. Exercise caution when everolimus is taken in combination with orally administered substrates of these enzymes and transporters, in particular, CYP3A4 substrates with a narrow therapeutic index. Co-administration with angiotensin-converting enzyme (ACE) inhibitors may increase the risk for angioedema based on results of a pooled analysis of randomized, double blind studies. Patient Care Implications: Patients taking everolimus should avoid the use of live vaccines and close contact with those who have received live vaccines. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
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8.4 veliparib (nsc 737664)

Chemical Name: 1H-Benzimidazole-7-carboxamide, 2-[(2R)-2-methyl-2-pyrrolidinyl]- Other Names:ABT-888, A-861695.0 Classification: Poly (ADP-ribosome) polymerase (PARP) Inhibitor CAS Registry Number: 912444-00-9 Molecular Formula: C13H16N4O **M.W.:** 244.29 Approximate Solubility: Freely soluble at pH < 6.9, soluble at pH 6.9 to 7.1, and slightly soluble at pH > 7.1. Mode of Action: Veliparib inhibits the formation of poly (ADP-ribose) (PAR) polymers in vitro and in vivo. It inhibits the repair of DNA when the DNA is damaged by cytotoxic agents.  
73 Veliparib increases antitumor efficacy when added to DNA-damaging therapies such as temozolomide. Description: White to light yellow solid.  
How Supplied: Veliparib capsules are available in 10 mg, 20 mg, 40 mg, and 50 mg immediate release capsules. The inactive ingredients are microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, gelatin, sodium lauryl sulfate, FD&C yellow \#5, and titanium dioxide. The capsules are packaged in HDPE bottles, and each HDPE bottle contains 16 capsules or 64 capsules.  
Veliparib capsules may be repackaged from the supplied HDPE bottles into amber (or other lowactinic) child resistant pharmacy dispensing bottles. Expiration will be 30 days from the repackaging date (or the original retest date, whichever is earlier) when stored at 15°C to 25°C (59°F to 77°F). Storage: Store the original bottle at 15º to 25ºC (59º to 77º F). Stability: Shelf-life stability studies for Veliparib capsules are ongoing. Route(s) **of Administration:** Oral Method of Administration: Administer Veliparib orally without regards to meals. Potential Drug Interactions: Clinical studies evaluating the metabolism of Veliparib have not been conducted. However, results from the in vitro analysis reveal that this agent is metabolized by multiple isoenzymes - CYP1A1, 2D6, 2C19, and 3A4. Veliparib is neither a potent inhibitor nor a potent inducer of the CYP-450 isoenzymes. Use caution when concomitantly administering with drugs that are substrate, inhibitor, or inducers of CYP1A1, 2D6, 2C19 and 3A4. Veliparib clears primarily in the urine as intact parent drug along with metabolites suggesting that renal function plays an important role in the drug clearance and its metabolites. Patient Care Implications: Patients may feel fatigue or tiredness. Loss of appetite and losing weight are common. Provide appropriate supportive care for diarrhea. Avoid long-sun exposure as it might exacerbate skin rash. Availability: Veliparib is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. Veliparib is provided to the NCI under a Collaborative Agreement between the Pharmaceutical Collaborator and the DCTD, NCI.
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8.5 azd1775 (nsc 751084)

Chemical Name: 2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-[4-(4-methylpiperazin1-yl)anilino] pyrazolo[3,4-d]pyrimidin-3-one hemihydrate Classification: Inhibitor of Wee1-kinase CAS: 277170-60-1 Molecular Formula: C27H32N8O2·0.5H2O **M.W.:** 518.623 Approximate Solubility: Aqueous solubility is 0.02 mg/mL. Mode of Action: AZD1775 is an inhibitor of the Wee1-kinase. Wee1 is a tyrosine kinase upstream of CDC2 thereby involved in regulation of cell cycle checkpoints, particularly the G2 checkpoint. As the majority of human cancers harbor abnormalities in the p53 pathway, they become more dependent on S- and G2-phase checkpoints. In preclinical models, AZD1775 selectively enhanced chemotherapy-induced death of cells deficient in p53 signaling.
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description azd1775 is a crystalline

How Supplied: AZD1775 is supplied by AstraZeneca and distributed by the Pharmaceutical  
 Management Branch, CTEP/DCTD/NCI as capsules available in 25 mg (yellow color, size 2 gelatin capsule) and 100 mg (orange color, size 2 gelatin capsule) strengths. Due to no further manufacturing, the 200 mg (light brown color, size 0 gelatin capsule) strength is available only as inventory allows until the shelf life is reached. The capsules consist of a roller compacted granule of agent, lactose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. Each high-density polyethylene (HDPE) bottle contains 20 capsules.
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storage store bottles at controlled

Stability: Shelf life studies of AZD1775 are on-going. Route **of Administration:** Oral administration. Take AZD1775 at least two hours before or two hours after a meal. Potential Drug Interactions: AZD1775 is primarily metabolized by CYP3A4 and is a weak, time-dependent inhibitor of CYP3A4. Avoid concomitant CYP3A4 moderate or strong inhibitors/inducers, and sensitive substrates with a narrow therapeutic index. AZD1775 is also a weak inhibitor of CYP2C19. Caution should be exercised with concomitant administration of sensitive substrates or substrates with a narrow therapeutic index.  
  of AZD1775 have not been performed. AZD1775 is not to be given to women who are pregnant or breast feeding.
Availability AZD1775 is an investigational agent supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. AZD1775 is provided to the NCI under a Collaborative Agreement between the Pharmaceutical Collaborator and DCTD, NCI.
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8.6 trametinib dimethyl sulfoxide (gsk1120212b)

Chemical Name (IUPAC): equimolecular combination of acetamide, N-[3-[3-cyclopropyl-5-[(2fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin1(2H)-yl]phenyl] with 1,1'-sulfinylbis[methane]
Other Names: trametinib, GSK1120212, JTP-74057, JTP-78296, JTP-75303, Mekinist CAS Registry Number: 1187431-43-1 Classification: MEK inhibitor Molecular Formula: C26H23FIN5O4 - C2H6OS **M.W.:** 693.53 Approximate Solubility: Trametinib dimethyl sulfoxide is almost insoluble in water (<0.0001 mg/mL at 25° C)
Mode of Action: Trametinib dimethyl sulfoxide is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. Tumor cells commonly have hyperactivated extracellular signal-related kinase (ERK) pathways in which MEK is a critical component. Trametinib dimethyl sulfoxide inhibits activation of MEK by RAF kinases and MEK kinases.  
Description: Trametinib dimethyl sulfoxide is a white to almost white powder.  
How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg (as free base) tablets. Each commercially-labeled bottle contains 30 tablets with a desiccant.  
The tablet core contains mannitol, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate (non-animal), colloidal silicon dioxide, and sodium lauryl sulfate.  
- 0.5 mg tablets are yellow, modified oval, biconvex and film-coated with 'GS' debossed on one face and 'TFC' on the opposing face. Aqueous film coating consists of hypromellose, titanium dioxide, polyethylene glycol, iron oxide yellow.  
- 2 mg tablets are pink, round, biconvex and film-coated with 'GS' debossed on one face and
'HMJ' on the opposing face. Aqueous film coating consists of hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80, iron oxide red.
Storage: Store tablets at 2°C -8°C in the original bottle. Do not repackage tablets or remove desiccant. Bottles should be protected from light and moisture.  
If a storage temperature excursion is identified, promptly return trametinib to 2°C -8°C and quarantine the supplies. Provide a detailed report of the excursion (including documentation of temperature monitoring and duration of the excursion) to PMBAfterHours@mail.nih.gov for determination of suitability.  
Stability: Refer to the package label for expiration.  
Route **of Administration:** Oral. Take by mouth on an empty stomach, either 1 hour before or 2 hours after a meal. If a dose of trametinib is missed, the dose can be taken if it is more than 12 hours until the next scheduled dose. Potential Drug Interactions: *In vitro* studies suggest that trametinib dimethyl sulfoxide is not a substrate of CYP enzymes or of human BCRP, MRP2, OATP1B1, OATP1B3, OATP2B1, OCT1, or MATE1 transporters. Trametinib elimination by deacetylation to metabolite M5 is dependent on carboxylesterases (CES1b, CES1c, and CES2). M5 is eliminated by CYP3A4 and other pathways, presenting the clinically relevant, albeit low, potential for drug-drug interaction. Trametinib is a substrate for P-gp and BSEP, but this is not expected to be clinically relevant due to trametinib's high permeability. Trametinib dimethyl sulfoxide is an *in vitro* inhibitor of CYP 2C8 and is anticipated to have overall low potential for drug interactions as a perpetrator. It is also a weak CYP3A4 inducer and expected to have little clinical effect on sensitive substrates. Trametinib is not an inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 3A4 and not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 MRP2 and MATE1. Patient Care Implications: Advise women study participants of reproductive potential to use effective contraception while receiving study treatment and for 4 months after the last dose of trametinib. Refer to the protocol document for specific guidance.
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8.7 agent ordering

NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned to the treatment arm prior to submitting the clinical drug request to PMB. NCI-supplied agents may be requested by eligible participating Investigators (or their authorized designee) at each participating institution. The CTEP-assigned protocol number must be used for ordering all CTEP-supplied investigational agents. The eligible participating investigators at each participating institution must be registered with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP-supplied investigational agents for the study should be ordered under the name of one lead participating investigator at that institution. Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of an "active" account status, a "current" password, and active person registration status. For questions about drug orders, transfers, returns, or accountability, call or email PMB any time. Refer to the PMB's website for specific policies and guidelines related to agent management.
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agent inventory records

The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, dispensing and final disposition of all agents received from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent Accountability Records for each agent, strength, formulation and ordering investigator on this protocol.
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investigator brochure availability

The current versions of the IBs for Everolimus, Veliparib, AZD1775, and Trametinib dimethyl sulfoxide will be accessible to site investigators and research staff through the PMB OAOP application. Access to OAOP requires the establishment of a CTEP IAM account and the maintenance of an "active" account status, a "current" password and active person registration status. Questions about IB access may be directed to the PMB IB Coordinator via email.
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useful links and contacts 9.

A mandatory pre-treatment tumor biopsy (2 cores) will be obtained from all patients after signing the consent and enrolling on the study to determine whether the tumor has a mutation in one of the pathways of interest, unless an FFPE block that meets Eligibility Criterion 3.1.2 is provided or a CLIA genetic testing report from a MATCH-designated lab is available and indicates an actionable mutation of interest. Patients entered on trial based on outside reports from MATCHdesignated labs will be biopsied during their first week on study for confirmatory screening with the Oncominev3 (MATCHv3) assay. Biopsy samples will be fixed in formalin and shipped as described in Section 9.3.  
Additionally, an optional tumor biopsy (2-5 cores) may be taken at or near the time of disease progression to assess for new acquired mutations.  
There is increasing awareness that biopsies lacking tumor of sufficient quantity or quality for analysis are a barrier to clinical research in both trials for which genetic sequencing establishes eligibility and in trials where paired pre- and post-treatment biopsies are collected to quantify
- CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
- NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov - PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm PMB Online Agent Order Processing (OAOP) application: https://ctepcore.nci.nih.gov/OAOP/
- CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/ - CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov
- IB Coordinator: IBCoordinator@mail.nih.gov
- PMB email: PMBAfterHours@mail.nih.gov
- PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET)
target modulation. In a retrospective analysis, we found that only 70% of the 18-gauge needle biopsies collected met pharmacodynamic assay quality control criteria due to necrosis, fibrosis, no or insufficient tumor content, and/or poor morphology; the success rate is only 50% when both pre- and post- treatment (paired) biopsies are required (Ferry-Galow et al., manuscript in preparation). The NCI is currently promoting efforts and providing resources to improve research biopsy quality given that insufficient tumor tissue samples compromise the scientific value of the study, the patients' contribution to research, and the staff resources devoted to clinical trials. Based on our experience, immediate and significant improvements in biopsy quality can be achieved simply from better communication with the interventional radiologists performing the biopsy procedures. We therefore recommend that participating site PIs invite their site's radiologists to join the research team and to review and discuss this protocol and the biopsy and specimen handling requirements. We recognize that these individuals are not always compensated for the additional time required to participate nor recognized for their effort, but at a minimum, communicating that research biopsies present requirements beyond those of biopsies collected for diagnostic purposes is of considerable value. Collecting multiple cores from each patient during each biopsy procedure increases the probability of obtaining sufficient samples for analysis, and the radiologist is best placed to determine how many cores are safe and feasible and evaluate patient willingness to continue donation. In the absence of a reliable and rapid method for "real-time" tumor content evaluation and given the need to preserve the tissue rapidly to ensure optimal sample quality, the interventional radiologist's judgment and experience are critical to procuring and preserving quality material.  
An adequate tumor biopsy sample will contain at least 50% tumor cells with minimal necrosis and stromal tissue; samples with less than 50% tumor cells will undergo tumor enrichment using a standardized macrodissection protocol. In case of samples with insufficient tumor content or DNA yield for analysis, the patient will be given the option to undergo a repeat tumor biopsy to obtain more tissue. Patients from whom sufficient tumor DNA material cannot be obtained for targeted analysis will be taken off-study.
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9.1.1 biopsy procedure

No more than three serial tumor biopsies will be obtained through Interventional Radiology by a percutaneous approach: one mandatory at screening baseline; one optional repeat biopsy if sufficient tumor DNA cannot be isolated at baseline; and one optional biopsy at time of disease progression (this biopsy may instead be collected on day 1 (± 2 days) of the cycle following any restaging at which a 10-19% increase in tumor volume is observed, per RECIST criteria, if the patient has been on study for at least 4 cycles). For eligibility determination, it is preferred that up to three core biopsies18-gauge in diameter and at least 1 cm in length are obtained. Only percutaneous biopsies will be performed on patients with solid tumors. However, excisional biopsy is allowed if indicated and can be used for analysis. Biopsies will be sent for analyses as defined in the protocol. It is estimated that there will be between 2-5 million cells from each biopsy. If a site is deemed appropriate for biopsy with minimal risk to the participant by agreement between the investigators and Interventional Radiology, an attempt at biopsy will be made. The biopsy procedure to be used in this protocol is described below; local anesthesia will be administered. Such biopsies can be safely performed as evidenced by literature reports [93] as well as our experience at the Clinical Center. Risks of the procedure include, but are not limited to, bleeding, infection, pain, and scarring. Each site will follow local Interventional Radiology SOPs for coagulant panel and platelets.  
- All biopsies will be by percutaneous approach unless excisional biopsy is indicated.  
- No biopsy by an invasive (endoscopic, laparoscopic, or surgical) procedure will be performed.
The use of imaging to facilitate biopsies will be decided by members of the Interventional Radiology team and may include ultrasound, CT scan, or MRI. Should CT scan be needed for biopsy, the number of scans for each procedure will be limited to the minimum number needed to safely obtain a biopsy. Tumor biopsies and local anesthesia will be administered only if they are considered to be of low risk to the participant as determined by the investigators and Interventional Radiology. If an initial attempt at percutaneous biopsy is unsuccessful, the patient will be given an option to proceed with a repeated attempt at percutaneous biopsy. If a pre-treatment biopsy sample is unable to be obtained for a given patient, or the patient chooses not to undergo the pre-treatment tumor biopsy, he/she must be taken off study because the genetic data from the tumor biopsy are essential to the primary objective of the trial.
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9.2 screening eligibility sample collection

At the NCI, the research nurse will contact the NCI Phase I/II PK/PD Support Group in NIH
Building 10 at least 24 hours prior to sample collection (E-mail: NCIPKPDsupportgroup@mail.nih.gov; Pager: 102-12798; Phone: 301-451-1169; Fax: 301-480-5871).  
The lab staff will be paged for sample pick-up. At the NCI only, 2-3 additional cores may be collected and snap frozen (see NCI Supplementary Appendix). Other participating sites should follow the sample collection instructions in Appendix E.  
Formalin jars (prefilled 30 mL) pre-labeled with the participant ID, biopsy date, protocol number, and site of tissue biopsy will be used for biopsy collection. Surgical tumor tissue and needle core biopsies (collected by 16-18-gauge needles) collected in neutral buffered formalin (one core per jar) will be shipped via overnight courier at ambient temperature on the day of biopsy collection to Dr. Mickey Williams' laboratory (MoCha) at the Frederick National Laboratory for Cancer Research (FNLCR) as defined in Appendix E.
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9.3 shipping for genetic analysis

For all patients, formalin-fixed tumor tissue or suitable FFPE block will be submitted for the genetic analyses described below. Genetic analysis will be done by the MoCha Laboratory. Samples labeled with unique patient IDs **only** will be sent directly to Dr. Mickey Williams' laboratory. Do NOT **include patient identifiers (e.g., medical** record number, patient name, **or initials) with the samples.** Please e-mail NCI-FrederickMPACTCLIA@mail.nih.gov if you have any questions about sample shipping. A sample shipping manifest is included in Appendix E. Following processing and paraffin embedding, one tissue section will be stained with H&E for histopathological examination by a designated pathologist. Tumor cellular content must be at least 50% and estimated tumor content will be recorded. The remaining biopsy will be extracted for nucleic acids using the Qiagen FFPET All-Prep procedure. DNA will be assessed for quantity and quality by spectroscopy (OD 260/280) and a PCR-based amplification quality assessment test. All specimens that meet necessary quantity and quality will be sequenced using a targeted sequencing assay. This assay will identify those mutations that are used for treatment assignment. If sufficient DNA is available from the tumor biopsy, whole-exome sequencing will be performed retrospectively for research purposes on samples unlinked from patient identifiers.
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9.3.2 blood samples for genetic

Whole blood samples will be collected to obtain plasma and mononuclear cells. All sequencing analysis from the plasma and mononuclear cells will be performed only after the samples are unlinked and stripped of the patient identifiers for retrospective research sequencing. The nucleic acid extracted from the unlinked patient's mononuclear cells will be sequenced to compare somatic mutational status to the tumor biopsy specimen. Plasma collected in this process will be delinked and used in exploratory research protocol to study (but not limited to), circulating tumor DNA. Two 10-mL cell-free DNA BCT (Streck) tubes should be collected on the same day as the screening eligibility biopsy (collection time can be either pre- or post-biopsy) and shipped at ambient temperature as described in Appendix E. The samples should be labeled with only the unique patient ID. Do NOT include patient identifiers (e.g., medical record number, patient name, **or initials) with the samples.** Please e-mail NCI-FrederickMPACTCLIA@mail.nih.gov if you have any questions about sample shipping. A sample shipping manifest is included in Appendix E. Upon receipt at the service laboratory, genomic DNA will be extracted for clinical targeted sequencing.
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9.4 sample handling and unlinking

Biospecimens will be collected and processed using locked SOPs that will ensure both specimen quality and patient confidentiality pursuant to informed consent provisions. Using a computerized inventory system, all specimen collection and processing steps will be documented and the specific location of each specimen will be tracked. Each new specimen collected will be assigned a unique barcode identifier that can be linked to the original specimen collected and other relevant information within the inventory system. To ensure patient confidentiality, only containers used for the initial specimen collections will be labeled with patient identifiers. Only the barcode identifier will be applied to all subsequent specimen containers. When specimens are processed and aliquoted, no patient information will be included on the new containers. Original specimen containers will be discarded. Only barcodelabeled specimens without patient identifiers will be shipped for analysis and/or storage.  
Specimen labels will indicate: CTEP protocol number 9149, unique patient accession number, 3digit sample number (see list below), collection time, and total volume collected, as appropriate. Samples from sets of at least three patients will be grouped for scientific analysis. Standardized 3-digit sample collection numbers: 300 series: blood for pharmacodynamics 500 series: tumor biopsies 800 series: blood for research (Streck tubes) The inventory process contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access to the inventory system and associated documents will be restricted to appropriate individuals. Requests to use specimens stored in the repository must be approved. The only patient information available in the inventory system will be the patient sex, diagnosis, and level of informed consent given. SOPs ensure that any changes in informed consent made by a patient and relayed to the PI will be reflected in the inventory system to ensure that specimens are destroyed as appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for high-quality performance. Any new use of these samples will require prospective IRB review and approval. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. If at any time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the patient, if so requested), and reported as such to the IRB. Samples which are unlinked cannot be traced to the individual patients, and the patient's request cannot be met. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample integrity (e.g., broken freezer allows for extensive sample thawing, etc.) will be reported as such to the IRB.
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9.4.1 sample unlinking

Clinical information linked to the unique patient IDs will be stored in a bioinformatics database along with the targeted sequencing panel. Once patient has completed treatment on study and has been taken off study, the unique patient ID will be deleted and a new random ID generated (arbitrary or random alphanumeric code) in the database by the bioinformatics team, thereby delinking the patient identifier from the information in the database. Patient consent to allow research use of his/her samples will be confirmed at this time. The Bioinformatics team will inform Dr. Mickey Williams' laboratory of the new random ID, all samples from a given patient will be transferred to the new ID, and Dr. Williams' lab will also break the link to the unique patient ID. The unique patient IDs will be discarded so there is no possibility of linking the samples to the sources.  
Dr. Williams' lab will proceed with (but not limited to) whole exome sequencing on deidentified samples for research purposes only. Data reports sent to the clinical site will be summary reports with no identifiable patient IDs whatsoever. When the study was re-opened with a new non-randomized design, a singular patient continued to receive randomized first-line study treatment. As of Amendment Y (January 7, 2020), sample unlinking (as described above) may occur while this patient remains on study treatment, if the patient consents to this change, in order to enable research-use analysis of samples in parallel with the other results from the randomized phase of the study.
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10. study calendar

Baseline evaluations are to be conducted within 8 days prior to start of protocol therapy. If the patient's condition deteriorates prior to initiation of treatment, evaluations should be repeated within 48 hours prior to initiating treatment. Scans and x-rays must be done within 28 days prior to the start of therapy. The start of the next cycle may be delayed for up to 1 week to accommodate scheduling conflicts. Treatments within a cycle may be delayed up to +/- 1 day to accommodate scheduling conflicts. Cycles may be continued until a patient meets one of the criteria in Section 5.6. Additional evaluations will be conducted as clinically indicated at the investigator's discretion.  
| PreStudy                                                                                                                                                        | Cycle 1   | Cycle 1                                                                                               | Cycle 1                         | Cycle 1         | Cycle 2   |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|-------------------------------------------------------------------------------------------------------|---------------------------------|-----------------|-----------|----|
| Week 1                                                                                                                                                 | Week 2    | Week 3                                                                                                | Week 4                          | onwards  Week 1 |           |    |
| Informed consent                                                                                                                                       | X         |                                                                                                       |                                 |                 |           |    |
| Tumor biopsy and blood  sample for genetic analysis                                                                                                    | X         |                                                                                                       |                                 |                 |           |    |
| Study Druga                                                                                                                                            | Xa        | Xa                                                                                                    | Xa                              | Xa              | Xa        |    |
| Demographics                                                                                                                                           | X         |                                                                                                       |                                 |                 |           |    |
| Medical historyb                                                                                                                                       | X         | X                                                                                                     |                                 |                 |           |    |
| Concurrent meds                                                                                                                                        | X         |                                                                                                       | X………………...………...………………...……...X |                 |           |    |
| Physical examb                                                                                                                                         | X         | X                                                                                                     | X                               |                 |           |    |
| Vital signsb                                                                                                                                           | X         | X                                                                                                     | X                               |                 |           |    |
| Height                                                                                                                                                 | X         |                                                                                                       |                                 |                 |           |    |
| Weightb                                                                                                                                                | X         | X                                                                                                     | X                               |                 |           |    |
| Performance status                                                                                                                                     | X         | X                                                                                                     | X                               |                 |           |    |
| CBC w/diff, pltsc                                                                                                                                      | X         | X                                                                                                     | X                               | X               | X         | X  |
| Serum chemistryc                                                                                                                                       | X         | X                                                                                                     | X                               | X               | X         | X  |
| EKGi                                                                                                                                                   | X         | X                                                                                                     |                                 |                 |           |    |
| Adverse event evaluation                                                                                                                               | X         |                                                                                                       | X……………..……………………..………………X       |                 |           |    |
| Tumor measurements are repeated every 2 cycles*                                                                                                        |           |                                                                                                       |                                 |                 |           |    |
| Radiologic evaluation                                                                                                                                  | X         | Documentation (radiologic) must be provided for patients  removed from study for progressive disease. |                                 |                 |           |    |
| -HCGd                                                                                                                                                 | X         | X                                                                                                     |                                 |                 |           |    |
| Ophthalmologic exame                                                                                                                                   | X         | X                                                                                                     |                                 |                 |           |    |
| ECHO/MUGAf                                                                                                                                             | X         |                                                                                                       |                                 |                 |           |    |
| Lipid monitoringg                                                                                                                                      | X         | Lipid monitoring every 2 cycles                                                                       |                                 |                 |           |    |
| Urinary Proteinh                                                                                                                                       | X         | X                                                                                                     |                                 |                 |           |    |
| a: Patients will be assigned to receive one of the following study drugs or drug combinations at  the assigned dose (cycles +/- 1 day for scheduling): |           |                                                                                                       |                                 |                 |           |    |  
a: Patients will be assigned to receive one of the following study drugs or drug combinations at the assigned dose (cycles +/- 1 day for scheduling):
- **Veliparib:** 40 mg orally BID qd days 1-7 plus temozolomide 150 mg/m2 orally qd days 15 (no food restrictions) in 28-day cycles. Patients who receive temozolomide will have an evaluation of their LFTs at the time of coming off-treatment.  
- **Everolimus:** 10 mg orally each day (no food restrictions) in 28-day cycles.  
- **Trametinib DMSO**: 2 mg orally each day either one hour before or two hours after a meal in 28-day cycles.  
- **AZD1775**: 225 mg orally BID x 5 doses either at least two hours before or two hours after a meal plus carboplatin (AUC 5) IV on day 1 of every 21-day cycle.  
b: History and physical, including vital signs and weight at the start of each cycle (up to 3 days before start of new cycle).  
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, glucose, phosphorus, potassium, SGOT[AST], SGPT[ALT], sodium, magnesium prior to treatment (up to 8 days prior) and as indicated. CBC w/diff, platelets and serum chemistries should be performed prior to cycle 1 treatment (up to 8 days prior), weekly throughout cycle 1, and at the start of each subsequent cycle (up to 3 days before start of new cycle). CBC with differential will be performed more frequently in patients with grade 4 neutropenia or thrombocytopenia until resolution to ≤ grade 3.  
d: Urine or serum pregnancy test (women of childbearing potential) pre-study. Repeat pregnancy test at the start of each subsequent cycle (up to 3 days before start of new cycle) for patients on AZD1775 only.  
e: Complete ophthalmologic examination at baseline for patients on MEK inhibitors only
(within 6 months prior to start of therapy), and at the start of the second cycle. Additional ophthalmologic exams may be performed as clinically indicated.  
f: Repeat echocardiograms for patients on trametinib DMSO or everolimus only, every 3 cycles.  
Additional echocardiograms may be performed as clinically indicated. The same modality (either ECHO or MUGA) should be used at baseline and at follow-up.  
g: Repeat lipid monitoring for patients on everolimus only (within 1 week prior to enrollment),
and every 2 cycles.  
h: Repeat urinary protein at baseline for patients on everolimus only (within 1 week prior to enrollment), and at the start of each subsequent cycle (up to 3 days before start of new cycle).  
i: Repeat EKGs at the start of each subsequent cycle (up to 3 days before start of new cycle) for patients on AZD1775 only.  
* CT scans can be performed every 4 cycles (for both the 21-day and 28-day cycles) for patients on study more than one year; it the patient changes therapy, CT scans will be performed once every 2 cycles for 1 year.  
Baseline evaluations are to be conducted within 8 days prior to start of protocol therapy. If the patient's condition deteriorates prior to initiation of treatment, evaluations should be repeated within 48 hours prior to initiating treatment. Scans and x-rays must be done within 28 days prior to the start of therapy. The start of the next cycle may be delayed for up to 1 week to accommodate scheduling conflicts. Treatments within a cycle may be delayed up to +/- 1 day to accommodate scheduling conflicts. Cycles may be continued until a patient meets one of the criteria in Section 5.4.
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11. measurement of effect 11.1

For the purposes of this study, patients should be re-evaluated every 2 cycles (every 4 cycles for patients on study more than one year). Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [94]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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11.1.1 definitions

Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with study drug. Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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11.1.2 disease parameters

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm by chest x-ray, as > 10 mm with CT scan, or > 10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated area might or might not be considered measurable. Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 86 disease, and abdominal masses (not followed by CT or MRI), are considered as nonmeasurable.  
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target** lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for nonnodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.
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11.1.3 methods for evaluation of

All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [9597]. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer [98]. Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.
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11.1.4 response criteria 11.1.4.1 evaluation

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or  
| non-target) must have reduction in short axis to  <10 mm.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                      |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Partial Response (PR):                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | At least a 30% decrease in the sum of the  diameters of target lesions, taking as reference  the baseline sum of diameters                                                                                                                                                                                                                                                                           |
| Progressive Disease (PD):                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | At least a 20% increase in the sum of the  diameters of target lesions, taking as reference  the smallest sum on study (this includes the  baseline sum if that is the smallest on study). In  addition to the relative increase of 20%, the sum  must also demonstrate an absolute increase of at  least 5 mm. (Note: the appearance of one or  more new lesions is also considered  progressions). |
| Stable Disease (SD):                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Neither sufficient shrinkage to qualify for PR  nor sufficient increase to qualify for PD, taking  as reference the smallest sum of diameters while  on study                                                                                                                                                                                                                                        |
| 11.1.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and  normalization of tumor marker level. All lymph  nodes must be non-pathological in size (<10  mm short axis) Note: If tumor markers are initially above the  upper normal limit, they must normalize for a  patient to be considered in complete clinical  response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s)  and/or maintenance of tumor marker level above  the normal limits Progressive Disease (PD): Appearance of one or more new lesions and/or  unequivocal progression of existing non-target  lesions. Unequivocal progression should not  normally trump target lesion status. It must be  representative of overall disease status change,  not a single lesion increase. |                                                                                                                                                                                                                                                                                                                                                                                                      |  
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).
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11.1.4.3 evaluation of best overall

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Target                                                                                                                   | Non-Target                                                                         | New       | Overall   | Best Overall Response when                        |
|--------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|-----------|-----------|---------------------------------------------------|
| Lesions                                                                                                                  | Lesions                                                                            | Lesions   | Response  | Confirmation is Required*                         |
| CR                                                                                                                       | CR                                                                                 | No        | CR        | > 4 wks. Confirmation**                           |
| CR                                                                                                                       | Non-CR/Non-PD                                                                      | No        | PR        |                                                   |
| CR                                                                                                                       | Not evaluated                                                                      | No        | PR        | > 4 wks. Confirmation**                           |
| PR                                                                                                                       | Non-CR/NonPD/not evaluated                                                                                    | No        | PR        |                                                   |
| SD                                                                                                                       | Non-CR/NonPD/not evaluated                                                                                    | No        | SD        | documented at least once >4 wks.  from baseline** |
| PD                                                                                                                       | Any                                                                                | Yes or No | PD        |                                                   |
| Any                                                                                                                      | PD***                                                                              | Yes or No | PD        | no prior SD, PR or CR                             |
| Any                                                                                                                      | Any                                                                                | Yes       | PD        |                                                   |
| *                                                                                                                        | See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. |           |           |                                                   |
| **                                                                                                                       | Only for non-randomized trials with response as primary endpoint.                  |           |           |                                                   |
| *** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as  disease progression. |                                                                                    |           |           |                                                   |  
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic deterioration."* Every effort should be made to document the objective progression even after discontinuation of treatment.  
| Non-Target Lesions                                                                                                                                                                                                                             | New Lesions   | Overall Response   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                                                                                                             | No            | CR                 |
| Non-CR/non-PD                                                                                                                                                                                                                                  | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                                                                                                              | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No     | PD                 |
| Any                                                                                                                                                                                                                                            | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is  increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category  when no lesions can be measured is not advised |               |                    |  
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
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11.1.5 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
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12. study oversight and data

This protocol is monitored at several levels, as described in this section. The Protocol Principal Investigator is responsible for monitoring the conduct and progress of the clinical trial, including the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious adverse events; reporting of expedited adverse events; and accumulation of reported adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and statistician have access to the data at all times through the CTMS web-based reporting portal. All Study Investigators at participating sites who register/enroll patients on a given protocol are responsible for timely submission of data via Medidata Rave and timely reporting of adverse events for that particular study. This includes timely review of data collected on the electronic CRFs submitted via Medidata Rave. All studies are also reviewed in accordance with the enrolling institution's data safety monitoring plan.
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safety monitoring committee

Because this is a multi-institutional protocol for which the NCI DTC is the coordinating center, it will be monitored by the DTC Safety Monitoring Committee (SMC).
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12.1 data reporting

Data collection for this study will be done exclusively through Medidata Rave. Access to the trial in Rave is granted through the iMedidata application to all persons with the appropriate roles assigned in the Regulatory Support System (RSS). To access Rave via iMedidata, the site user must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA, or Rave Investigator) on either the LPO or participating organization roster at the enrolling site. To hold the Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an AP registration type. To hold the Rave Investigator role, the individual must be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave. Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the iMedidata screen. Users that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU members' website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com.
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12.1.1 method

This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if approved by CTEP). Information on CTMS reporting is available at http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. Onsite audits will be conducted three times annually (one annual site visit and two data audits). For CTMS monitored studies, after users have activated their accounts, please contact the Theradex Help Desk at (609) 619-7862 or by e-mail at CTMSSupport@theradex.com for additional support with Rave and completion of CRFs.
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12.1.2 responsibility for data submission

For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and that protocol specified data are submitted accurately and in a timely manner to the CTMS via the electronic data capture system, Medidata Rave. Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. For Institutional Performance Monitoring, data will be considered delinquent if it is greater than 4 weeks past due. Data from Medidata Rave and CTEP-AERS are reviewed by the CTMS on an ongoing basis as data is received. Queries will be issued by CTMS directly within Rave. The queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI policies and procedures with the overarching goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may be found on the CTEP (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and CTSU websites. An End of Study CRF is to be completed by the PI, and is to include a summary of study endpoints not otherwise captured in the database, such as (for phase 1 trials), and a description of any dose-limiting toxicities (DLTs). CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository (caDSR) compliant
(http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-andsemantics/metadata-and-models). Customized eCRFs will be included when appropriate to meet unique study requirements. The PI is encouraged to review the eCRFs, working closely with CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs prior to study activation. CTMS will prepare the eCRFs with built-in edit checks to the extent possible to promote data integrity. CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly basis. The trial's lead institution is responsible for timely submission to CTMS via Rave, as above. Further information on data submission procedures can be found in the ETCTN Program Guidelines
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm).
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12.2 cooperative research and development

The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the "Intellectual Property Option to Collaborator" (http:// ctep.cancer.gov/industry) contained within the terms of award, apply to the use of the Agent(s) in this study:
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing investigational Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient's family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov.  
2. For a clinical protocol where there is an investigational Agent used in combination with
(an)other investigational Agent(s), each the subject of different collaborative agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data."): a. NCI will provide all Collaborators with prior written notice regarding the existence and nature of any agreements governing their collaboration with NIH, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.  
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own investigational Agent.  
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the MultiParty Data solely for development, regulatory approval, and commercialization of its own investigational Agent.  
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order as described in the IP Option to Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, all Clinical Data and Results and Raw Data will be collected, used, and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the *Standards for Privacy of Individually* Identifiable Health Information set forth in 45 C.F.R. Part 164.  
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.  
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.  
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days to ensure that Collaborator's confidential and proprietary data, in addition to Collaborator(s)'s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: E-mail: ncicteppubs@mail.nih.gov The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator's confidential/ proprietary information.
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12.3 publication policy

Recognizing the need to make clinical trial outcomes rapidly available to the cancer clinical trials community [99], publication of the results from this study will be a priority following completion of accrual, follow up, and data analyses. Authorship of this group-wide study will include the Coordinating Center PI, the study statistician, and one representative from each participating institution listed on the cover page of the protocol that contributed more than 10% of the eligible, evaluable cases. The first author, last author, corresponding author(s), and study statistician, will all be NCI investigators. The CTEP medical monitor will also be listed as an author. Lead investigators from laboratories involved in conducting correlative studies will be listed as authors if data from their laboratories are included in the clinical results manuscript. If several investigators were responsible for a participating institution's accrual, the designated representative from that institution ordinarily will be the PI. When an individual other than the PI is largely responsible for a participating institution's accrual, the PI is expected to substitute that individual as an author in place of himself/herself. The intent is to offer recognition to the individuals who have been most directly involved in the study. Because the Coordinating Center PI will often be unaware of the relative contributions of investigators at each institution, the PIs at participating institutions accruing more than 10% of cases will be solicited routinely to determine whether another individual should be substituted for them in authorship. There will be only one author from each of the participating institutions listed on the cover page of the protocol. If the PI is already an author, based on scientific contribution to the study, a second person from that PI's institution will not automatically be accepted for authorship based on institutional accrual. This protocol includes several correlative studies that may be published with the group-wide clinical results paper or as separate, stand-alone scientific papers. The decision to publish correlative study papers separately will be made by the Coordinating Center PI and relevant correlative study investigators, and will be subject to the Collaborative Agreement for study publications described in Section 12.3. Authorship of the correlative results paper will include the Coordinating Center PI, the correlative study lead investigators, and researchers from the correlative studies laboratories nominated by the correlative study lead investigators. Correlative study lead investigators may also nominate authors who have contributed to the feasibility of the study and/or the development of assays and procedures that supported evaluation of study samples. The final decision on the authorship of any manuscripts related to this trial will be made by the Coordinating Center PI.
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13. statistical considerations

This is a multi-histology pilot trial with patients enrolled into multiple cohorts. Up to 30 patients will be treated within each of the targeted agent cohorts. All eligible patients who have initiated treatment will be included in the OR and PFS analyses within each agent cohort in which objective response rate and PFS (as a secondary endpoint) will be assessed against the historical standards of 5% response rate and 25% 4-month PFS. We will allow patients to be entered on trial and begin treatment based on CLIA genetic testing reports from MATCH-designated labs indicating actionable mutations of interest in study DNA damage repair genes. On-study biopsies will be collected from these patients for study confirmatory screening with the Oncominev3 (MATCHv3) assay. Those whose aMOIs cannot be confirmed can choose to remain on study and receive study drugs but will not be counted as eligible or included in the primary efficacy analysis or the futility analysis. 1. Within each agent cohort, up to 30 eligible patients will be accrued, to discriminate between tumor response rates of 20% vs. 5%. If at least 4 objective responses (at least 13%) are observed among the 30 patients, this agent will be considered promising for this mutation category. If no objective responses are observed among the initial 12 eligible patients, beginning, for the veliparib plus temozolomide arm, with Amendment U), the cohort will be terminated early. Accrual to the cohort will be paused after accrual of the initial 12 eligible patients until at least 1 objective response is observed. This design yields at least 88% power to detect a true objective response rate of at least 20%. It yields at least .94 probability of a negative result if the true objective response rate is no more than 5%. As a secondary endpoint, 4-month PFS will be evaluated. If at least 12 instances of 4-month PFS (at least 40%) are observed among the 30 patients, 4-month PFS will be considered promising. This will occur with 90% likelihood if the true 4-month PFS rate is 50% (median PFS of 4 months) and with 5% likelihood if the true 4-month PFS rate is 25% (median PFS of 2 months).