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To: CTEP Protocol and Information Office  
| From:   | Alice Chen, MD, DTC, NCI                                                                                                    |
|---------|-----------------------------------------------------------------------------------------------------------------------------|
| Re:     | Amendment to Protocol 9149: Molecular Profiling-based Assignment of Cancer  Therapy for Patients With Advanced Solid Tumors |  
Date: January 7, 2019  
With this amendment, we are incorporating recommendations from CTEP's review of protocol version 02/06/2019, and making some administrative changes. We would also like to update the protocol to allow the sole patient who continues to receive randomized Trametinib DMSO treatment (22+ cycles) to consent to having her mutational status and arm assignment (i.e., experimental or control) disclosed to herself and/or her treating physician now, rather than wait until disease progression, given the new non-randomized study design and statistical analysis plan. We would also like to allow this patient to consent to sample unlinking while she remains on study, in order to enable research-use analysis of her sample in parallel with the other results from the randomized portion of the study. Thank you for your consideration.
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i. recommendations from ctep review

| #   | Section   | Comments                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|-----|-----------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.  | 12.1      | Please revise the following paragraph as indicated. 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) (Rave CRA, Read-Only, CRA, Lab Admin, SLA, or Site  Investigator) on either the LPO or participating organization roster at the enrolling  site. To hold the Rave CRA role or Rave CRA (Lab Admin) Rave CRA role or  CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold the Rave Site Investigator role, the individual must be registered as an  NPIVR or IVR. Associates can hold read-only roles in Rave.  PI Response: We have revised the paragraph as indicated. |
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ii. other protocol changes

| #   | Section    | Comments                                       |
|-----|------------|------------------------------------------------|
| 2.  | Cover Page | Updated the protocol version date and letters. |  
| #   | Section                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Comments                                                                                                                                                                                                                                                                                       |
|-----|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3.  | Cover Page                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Updated the list of Associate Investigators.                                                                                                                                                                                                                                                   |
| 4.  | 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Given the new non-randomized study design and statistical analysis                                                                                                                                                                                                                             |
| 5.2 | plan, we would like to revise and update the protocol to allow the sole  patient who continues to receive randomized Trametinib DMSO  treatment (22+ cycles) to consent to having her mutational status and  arm assignment (i.e., experimental or control) disclosed to herself and/or  her treating physician now, rather than wait until disease progression to  find out per the original study plan. The patient, in discussion with the  treating physician, will have the same on-study treatment options at  progression as before, but because she is unblinded we think she will  have better information sooner about her future treatment options. |                                                                                                                                                                                                                                                                                                |
| 5.  | 9.4.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Revised the sample unlinking procedure to allow sample unlinking for  the sole remaining randomized patient to occur while the patient remains  on study, in order to enable research-use analysis of her sample in  parallel with the other results from the randomized portion of the study. |
| 6.  | Appendix F                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Replaced the Biopsy Sequencing Results and Analysis Form with an  updated form supplied by the MoCha lab. .                                                                                                                                                                                    |  
Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors Abbreviated Title: MPACT  
| Coordinating Center:      | LAO-NCI/National Cancer Institute LAO National Cancer Institute  10 Center Drive, 12N226 Bethesda, MD 20892                                                                                                                                                                                                         |
|---------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Principal Investigator:   | A. P. Chen, MDA-E Developmental Therapeutics Clinic (NCI DTC MM) 31 Center Drive, Bldg 31, Room 3A44 Bethesda, MD 20892 Phone: (240) 781-3320 Fax: (240) 541-4515 chenali@mail.nih.gov                                                                                                                              |
| NCI Co-Investigators:     | James H. Doroshow, MD, DCTDA-E Richard Piekarz, MD, PhD, DCTDA-E Geraldine O'Sullivan Coyne, MD, PhD, DCTDA-E Howard Streicher, MD, DCTDA-E Naoko Takebe, MD, PhD, DCTDA-E Arjun Mittra, MD, DCTDA-E Sheila Prindiville, MD, MPH, DCTDA-E Rafeh Naqash, MD, DCTD/ NCIA-E Jessica Mukherjee, MS, CRNP, DCTD/NCIA,B,E |
| Non-NCI Co-Investigators: | Lamin Juwara CRNP, Leidos Biomed., FNLCRA,B,E P. Mickey Williams, PhD, Leidos Biomed., FNLCRF                                                                                                                                                                                                                       |
| Referral Contact:         | Nancy Moore, RN, DCTDA,B,E Bldg 10/Rm 13N-214 (240) 760-6045 Fax: (301) 451-5625 nancy.moore@nih.gov                                                                                                                                                                                                                |  
Roles: A*obtains information by intervening or interacting with living individuals for research purposes;*
Bobtains identifiable private information about living individuals; C*obtainsthe voluntary informed* consent of individuals to be subjects; Dmakes decisions about subject eligibility; E*studies, interprets, or* analyzes identifiable private information or data/specimens for research purposes; F*reviews patient* genetic sequencing data but is not involved in clinical care Participating Organizations:  
| LAO-11030 / University Health Network Princess Margaret Cancer Center LAO LAO-CA043 / City of Hope Comprehensive Cancer Center LAO LAO-CT018 / Yale University Cancer Center LAO LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO LAO-MN026 / Mayo Clinic Cancer Center LAO LAO-NC010 / Duke University - Duke Cancer Institute LAO LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO LAO-PA015 / University of Pittsburgh Cancer Institute LAO LAO-TX035 / University of Texas MD Anderson Cancer Center LAO   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Statisticians: Larry Rubinstein, PhDE
9609 Medical Center Dr.   
  
 9609 Medical Center Dr. Rockville, MD 20850 Phone: (240) 276 7385 fosterjc@nih.gov NCI-supplied Agents: AZD1775 (NSC 751084)
Veliparib (NSC 737664) Trametinib DMSO (NSC 763093) Everolimus (NSC 733504) Temozolomide (NSC 362856)
Carboplatin (NSC 241240) IND Number: 116976 Version Date: January 7, 2020 (Amendment Y, iRIS V)
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precis background

- Targeted therapy based on identifying underlying genetic aberrations within the tumor is the goal of personalized medicine. This pilot trial aims to establish whether advanced cancer patients who have no treatment options with proven benefit, and with tumor mutations in one of 3 genetic pathways (DNA repair, PI3K, or RAS/RAF/MEK) are more likely to derive clinical benefit if treated with agents targeting that pathway than if treated with agents that do not. Each patient will be randomly assigned to receive the recommended Phase II dose of either a study drug identified to work on their tumor's mutation/aberrant pathway, or an agent from the complementary set not identified to work on the mutations of interest. *As of* Amendment U, only the DNA repair arm remains open *to accrual.*
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objectives

- Evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers.
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eligibility

- Adult patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy and/or for which no standard treatment is available that has been shown to improve survival.  
- Tumor amenable to percutaneous biopsy, and willingness to undergo tumor biopsy.
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study design

- Patients enrolled on study will have a tumor biopsy sequenced in a CLIA-certified lab for specific mutations of interest in DNA repair pathways. If such mutations are not detected, the patient will be taken off study. Eligibility may also be determined from existing CLIA genetic testing reports from a MATCH-designated CLIA lab.  
- Patients who have received PARPi in combination with temozolomide are not eligible.  
- Patients in whom a mutation of interest is detected will receive an agent prospectively identified to target that mutation/pathway
- Targeted drugs will be administered at recommended Phase II doses and schedules: (1)
Veliparib (PARP inhibitor) with temozolomide for defects in the DNA repair pathway; (2) AZD1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathway; (3) Everolimus (mTOR inhibitor) for mutations in the PI3K pathway; or (4) Trametinib DMSO (MEK inhibitor) for mutations in the RAS/RAF/MEK pathway. As of Amendment U, only the Veliparib with temozolomide arm remains open to accrual.  
- Given the relative frequencies of the mutations, up to 100 patients will need to be enrolled to acquire 30 evaluable patients per open arm.  
  
SCHEMA
a Tumor biopsy (mandatory) will be performed on all patients enrolled on study; tissue will be sequenced for the presence of specific mutations of interest. Patients with qualifying MATCHdesignated lab genetic testing reports may also be eligible.  
b Only patients with specified mutations of interest will be administered targeted drug at recommended Phase II doses and schedules (see page 5). One additional optional tumor biopsy may be performed at time of disease progression on study to assess for new mutations. (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).  
  
Patients with specified mutations of interest will be assigned to receive the following study drug combination at the assigned dose. Cycle length is +/- 1 day for scheduling:
- **Veliparib** 40 mg orally BID qd days 1-7 plus **temozolomide** 150 mg/m2 orally qd days 1-5 (no food restrictions) in 28-day cycles
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table of contents

| PRÉCIS .                                                                                                                          |                                                                                                                                                  |
|-----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA                                                                                                                            |                                                                                                                                                  |
| TABLE OF CONTENTS.                                                                                                                |                                                                                                                                                  |
| 1.                                                                                                                                | OBJECTIVES                                                                                                                                       |
| 1.1                                                                                                                               | Primary                                                                                                                                          |
| 2.                                                                                                                                | BACKGROUND .                                                                                                                                     |
| 2.1                                                                                                                               | Targeted Mutations and Pathways                                                                                                                  |
| 2.2                                                                                                                               | Targeted Genes/Locus Selection                                                                                                                   |
| 2.3                                                                                                                               | Study Agents                                                                                                                                     |
| 2.4                                                                                                                               | Study Disease                                                                                                                                    |
| 2.5                                                                                                                               | Genetic Sequencing Research Ethics and NIH Genomic Data Sharing Policy ................ 18                                                       |
| 2.6                                                                                                                               | RATIONALE FOR THE STUDY ......................................................................................................................20 |
| 3.                                                                                                                                | PATIENT SELECTION (TUMOR SEQUENCING/DRUG TREATMENT)...................20                                                                         |
| 3.1                                                                                                                               | Eligibility Criteria: Tumor Biopsy Sequencing .......................................................................21                          |
| 3.2                                                                                                                               | Exclusion Criteria: Tumor Biopsy Sequencing.........................................................................22                           |
| 3.3                                                                                                                               | Eligibility Criteria: Targeted Treatment .....................................................................................23                 |
| 3.4                                                                                                                               | Exclusion Criteria: Targeted Treatment .................................................................................25                       |
| 3.5                                                                                                                               | Evaluation for Enrollment for Tumor Biopsy Screening .....................................................26                                     |
| 3.6                                                                                                                               | Evaluation for Treatment on Study ....................................................................................26                         |
| 4.                                                                                                                                | REGISTRATION PROCEDURES .................................................................................................27                      |
| 4.1                                                                                                                               | Investigator and Research Associate Registration with CTEP                                                                                       |
| 4.2                                                                                                                               | Site Registration ............................................................................................................................27 |
| 4.3                                                                                                                               | General Guidelines                                                                                                                               |
| 4.4                                                                                                                               | Randomization Procedures (N/A)                                                                                                                   |
| 5.                                                                                                                                | TREATMENT PLAN                                                                                                                                   |
| Study Design                                                                                                                      |                                                                                                                                                  |
| 5.1                                                                                                                               |                                                                                                                                                  |
| 5.2                                                                                                                               | Targeted Therapy Arms ................................................................................................................31         |
| 5.3                                                                                                                               | Agent Administration .                                                                                                                           |
| 5.4                                                                                                                               | General Concomitant Medication and Supportive Care Guidelines:                                                                                   |
| 5.5                                                                                                                               | Definition of Off-Study Parameters                                                                                                               |
| 5.6                                                                                                                               | D DURATION OF FOLLOW-UP                                                                                                                          |
| 5.7                                                                                                                               | Criteria for Removal From Study                                                                                                                  |
| 6.                                                                                                                                | DOSING DELAYS/DOSE MODIFICATIONS ..................................................................36                                            |
| 6.1                                                                                                                               | Dose Modifications ...................................................................................................................36         |
| 6.2                                                                                                                               | Agent-specific Dose Modifications: Trametinib DMSO..................................................37                                           |
| 6.3                                                                                                                               | Agent-specific Dose Modifications: Everolimus ............................................................47                                     |
| Agent-specific Dose Modifications: Veliparib ..................................................................................51 |                                                                                                                                                  |
| 6.4                                                                                                                               |                                                                                                                                                  |
| 7.                                                                                                                                | ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS                                                                                                  |
| 7.1                                                                                                                               | Comprehensive Adverse Events and Potential Risks Lists (CAEPRs)                                                                                  |
| 7.2                                                                                                                               | Adverse Event Characteristics                                                                                                                    |
| 7.3                                                                                                                               | Expedited Adverse Event Reporting                                                                                                                |
| 7.4                                                                                                                               | Routine Adverse Event Reporting                                                                                                                  |
| 7.5                                                                                                                               | Secondary Malignancy                                                                                                                             |
| 7.6                                                                                                                               | Second Malignancy                                                                                                                                |
| 8.                                                                                                                                | PHARMACEUTICAL INFORMATION                                                                                                                       |
| 8.1                                                                                                                               | Temozolomide (NSC 362856)                                                                                                                        |
| 8.2                                                                                                                               | Carboplatin (NSC 241240)                                                                                                                         |
| S                                                                                                                                 |                                                                                                                                                  |  
| 8.3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Everolimus (NSC 733504) 72                                                                 |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|
| 8.4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Veliparib (NSC 737664) 73                                                                  |
| 8.5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | AZD1775 (NSC 751084) 74                                                                    |
| 8.6                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 76                                |
| 8.7                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Agent Ordering 77                                                                          |
| 9.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | GENETIC ANALYSIS 78                                                                        |
| 9.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Tumor Biopsies 78                                                                          |
| 9.2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Screening Eligibility Sample Collection and Processing 80                                  |
| 9.3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Shipping for Genetic Analysis 81                                                           |
| 9.4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Sample Handling and Unlinking Procedures 82                                                |
| 10.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | STUDY CALENDAR: 83                                                                         |
| 11.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | MEASUREMENT OF EFFECT 86                                                                   |
| 11.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Antitumor Effect - Solid Tumors 86                                                         |
| 12.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS 92                            |
| 12.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Data Reporting 92                                                                          |
| 12.2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement  (CTA) 94 |
| 12.3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Publication Policy 96                                                                      |
| 13.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | STATISTICAL CONSIDERATIONS 97                                                              |
| 13.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Sample Size/Accrual Rate 97                                                                |
| 13.2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Analysis of Additional Endpoints 97                                                        |
| 14.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | HUMAN SUBJECTS PROTECTIONS 98                                                              |
| 14.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Rationale for Subject Selection 98                                                         |
| 14.2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Justification for Exclusions 99                                                            |
| 14.3                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Evaluation of Benefits and Risks/Discomforts 99                                            |
| 14.4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Consent and Assent Process and Documentation 99                                            |
| 14.5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Procedure for Protecting Against or Minimizing Any Potential Risks 100                     |
| 15.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | REFERENCES 101                                                                             |
| APPENDIX A: Performance Status Criteria 106 APPENDIX B: Potential Drug Interactions and Drug Information Handouts 107 APPENDIX C: Medications That May Cause QTc Prolongation 116 APPENDIX D: Patient Study Diaries 118 APPENDIX E: MPACT (9149) Sample Shipping Instructions and Manifest 131 APPENDIX F: Biopsy Sequencing Results and Analysis Form 133 APPENDIX G: Molecular Tumor Board Members 136 APPENDIX H: Example Tumor Variant Patient Report 137 APPENDIX I: Veliparib plus Temozolomide (Proprietary Information) 138 APPENDIX J: AZD1775 (Proprietary Information) 141 APPENDIX K: Trametinib DMSO (Proprietary Information) 145 APPENDIX L: NCI Correlative Imaging Studies 150 |                                                                                            |
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1. objectives 1.1 primary 2.

Evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers. The initial design of this targeted pilot trial was to establish whether patients with tumor mutations in one of the genetic pathways of interest (DNA repair, PI3K, or RAS/RAF/MEK) are more likely to derive clinical benefit (defined as objective response or progression-free survival) if treated with agents targeting that specific pathway than with agents that do not. The study design was developed in conjunction with experts in clinical trial design, genetic sequencing, molecular oncology, cell biology, and statistics, who developed an algorithm that defines clinical action based on genetic variants reported in the genes of interest (Table 1 and Section 2.2). Aberrations in the PI3K-Akt, KRAS and RAF/MEK/ERK pathways and defects in the DNA repair pathways are common in several cancers. Each of these pathways and the selected targeted agents are discussed below. The genes of interest and mutations to be analyzed have been prospectively defined based on the recommendations of the multidisciplinary Molecular Tumor Board convened for this study (membership list included in Appendix G). This study was placed on hold in January 2018 for interim futility analysis of the AZD1775 plus carboplatin and Trametinib DMSO arms (see Section 13), at which time a total of 193 patients had biopsies collected for screening and 99 (51%) had an actionable mutation of interest for randomizing to study drug. The major conclusions from this analysis are summarized below; a manuscript describing study results is in progress: 1. No confirmed objective responses were measured among the initial 18 patients of the AZD1775 plus carboplatin cohort; this cohort was terminated in March 2018.  
2. One confirmed response was measured among 20 patients starting treatment on the Trametinib DMSO experimental cohort (accrual beyond 12 patients was due to delayed outcome reporting from participating sites); this cohort was terminated in March 2018.  
3. There were insufficient numbers of patients treated on the everolimus experimental cohort to assess response rate, but no responses were measured; this cohort was terminated in March 2018.  
4. There were insufficient numbers of patients treated on the veliparib plus temozolomide arm to assess response rate, but no responses were measured; however, the study team have revised the eligibility criteria to include BRCA mutations, which is projected to increase the hit rate.  
5. Using the percentage of patients who started their assigned treatment as a measure of compliance, the overall percentage of patients assigned to experimental arm B who elected not to receive treatment was 47%, unexpectedly higher than the rate for patients assigned to experimental arm A (23%) (p=.02, 1-sided, by Fisher exact test). Interim analysis therefore suggests that patients at participating sites were choosing not to participate on the assigned control arm because *a priori* knowledge of their mutations of interest (e.g., from FoundationOne reports) led to expectation of treatment assignment. Our hypothesis, that conducting genetic analysis and choosing targeted therapy based on genomic analysis will result in improved response rate and PFS, cannot be evaluated in light of this—indeed, the utility of the randomized phase 2 design to determine whether targeted therapy based on presence of drug-susceptible tumor mutations will result in improved response rate is clearly in doubt [1]. Based on these data it was determined that the study will reopen without randomization; patients with actionable mutations of interest will be assigned to targeted treatment arm(s) to assess the proportion of patients with objective response. The performance of each individual mutational status cohort will be compared to that of historical controls.  
With the current non-randomized study design and statistical analysis plan, there is less of a rationale for blinding randomized patients, treating physicians, and the study team to the actual sequencing data until disease progression. As of Amendment Y (January 7, 2020) one patient who was randomized to the Trametinib DMSO cohort under the original study design remains on treatment with prolonged stable disease (22+ cycles), blinded to sequencing results and arm assignment. Amendment Y allows this patient to consent to having her mutational status and arm assignment (i.e., experimental or control) disclosed to herself and/or her treating physician now, rather than waiting until disease progression. The study team would also be informed. The patient, in discussion with the treating physician, will continue to have the option to receive the other study treatment prospectively identified to work on the identified mutation/pathway per the original study design if she is currently on the control arm. As noted above, the responses in the experimental cohorts were insufficient to indicate that a patient is more likely to derive clinical benefit if treated with agents targeting that pathway than if treated with agents that do not. The agents and respective pathways being evaluated in this study are:  
1. Veliparib (PARP inhibitor) with temozolomide for defects in DNA repair pathways 2. AZD1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathways *(closed* March 2018)
3. Everolimus (mTOR inhibitor) for mutations in the PI3K pathway *(closed March 2018)* 4. Trametinib DMSO (MEK inhibitor) for mutations in the RAS/RAF/MEK pathway
(closed March 2018)
Genetic sequencing will be performed in the CLIA-certified Molecular Characterization Laboratory at the Frederick National Laboratory for Cancer Research (FNLCR). In view of the complexity of information collected, each patient's data will be reviewed by investigators indicated with an F on the cover page or (in their absence), their designees for internal consistency. The genetic variants to be assessed and treatment algorithms have been prospectively defined to proceed with assigning specific treatments to the patients on study. The potential risks associated with obtaining genetic information are discussed in Section 2.5. Patients with CLIA tumor reports from Foundation Medicine (FoundationOne), CARIS
(Molecular Intelligence), or other EAY131 MATCH-Designated Laboratories (https://ecogacrin.org/nci-match-eay131-designated-labs) may be eligible if they have a study actionable mutation. At the NCI only, every attempt will be made to collect standard-of-care images (CT or MRI) that qualified the patient for inclusion in this trial, along with the images taken during image-guided biopsy, and any follow up imaging studies during restaging (optional), will be collected to allow research into correlation of the image phenotypic features with the genomic analyses, an area of active research in radiology [2] [3]. All images will be de-identified of personal health information at the CCR Molecular Imaging Program before leaving the NIH Clinical Center site and will be stored in The Cancer Imaging Archive (http://www.cancerimagingarchive.net/), an NIH policy-compliant internet-accessible collection, with controlled access. The process is defined in Appendix L.
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2.1 targeted mutations and pathways

DNA damage by traditional chemotherapeutic agents does not always result in cell death due to complex DNA repair pathways. Recent research has suggested that directly targeting DNA repair pathways may result in effective killing of tumor cells, particularly in patients with pre-existing defects in DNA repair pathways. There are 6 major DNA repair pathways: direct repair (DR), base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and nonhomologous end-joining (NHEJ) [4]. Each pathway consists of a complex interaction of different molecular characteristics (Figure 1).  
  
The BER pathway exerts its biological role by removing bases that have been damaged and plays a vital role in repairing DNA single-strand breaks (SSBs) caused by DNA-
damaging factors such as anticancer agents [5].  This pathway includes the poly(ADP- ribose) polymerase (PARP) family of enzymes.  PARP-1 and -2 are the most abundant of the PARPs and are essential nuclear enzymes that play a role in recognition of DNA damage and facilitation of DNA repair [6, 7].  PARP-1 and -2 bind rapidly to sites of DNA SSBs, which leads to the separation of PARP from DNA.  This leads to modulation of DNA damage response proteins (XRCC1/ligase III complex, Polβ) that bind to sites of DNA damage.  Double-strand breaks (DSBs) are also strong activators of PARP-1, resulting in  PARP-1–mediated activation of DNA-PK and Ku80, important components of NHEJ repair pathway [8, 9].  Inhibition of PARP sensitizes tumor cells to cytotoxic agents (e.g., temozolomide) which induce DNA damage that would normally be repaired through the BER system.  PARP inhibitors do not potentiate agents that do not cause DNA damage.  
Expression of PARP is higher in tumor cells than normal cells.  This overexpression has been linked to drug resistance and the ability of tumor cells to withstand genotoxic stress.  
In knockout mouse models, deletion of PARP-1 is sufficient to impair DNA repair [1012].  Hence, it is anticipated that PARP inhibitors will function as sensitizing agents for chemotherapy and radiation therapy administered to induce DNA damage. Recent data preclinical data that isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations induce a homologous recombination defect and a sensitivity to PARP inhibition suggest that these targets may have may have therapeutic relevance [13]. Wee1 is a tyrosine kinase implicated in the inhibitory phosphorylation of CDK1/CDC2bound cyclin B complex responsible for G2 arrest [14]. Originally identified in fission yeast [15], wee 1 deficiency resulted in premature mitotic entry and replication of smaller-sized yeast. Wee1 belongs to a family of protein kinases involved in the terminal phosphorylation and inactivation of (CDK1/CDC2)-bound cyclin B via phosphorylation of its Tyr15 residue near the ATP-binding pocket, resulting in G2 cell cycle arrest in response to DNA damage. Wee1 overexpression has been demonstrated in hepatocellular carcinoma [16], luminal and HER-2 positive breast cancers [17], colon, lung carcinoma, and seminoma tumor samples [18].
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2.1.2 mutations in the ras

MEK is a critical kinase in the mitogen-activated protein (MAP) kinase signal transduction pathway for many growth factor receptors that provide growth signals to cancer cells, including epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGFR1), and platelet-derived growth factor receptor. Cell signaling through growth factor receptors and protein kinases plays an essential role in cell survival, proliferation, and differentiation. The RAS/RAF kinase pathway is one of the most important and best understood MAP kinase pathways involved in normal and uncontrolled cell growth. In proliferative diseases, genetic mutations and/or over expression of growth factor receptors, downstream signaling proteins, or protein kinases involved in the RAS/RAF MAP kinase pathway lead to uncontrolled cell proliferation and, eventually, tumor formation. RAS:RAF association promotes translocation of the normally cytoplasmic RAF protein to the plasma membrane, resulting in activation of its kinase function. Constitutive activation of the RAS pathways occurs through mutation activation of the RAS oncogene or of downstream effectors of RAS [19]. Mutated, oncogenic forms of RAS are found in 50% of colon and >90% of pancreatic cancers [20], as well as many others types of cancers [21], including 15 to 30% of non-small cell lung cancer (NSCLC) [22].  
  
KRAS mutations, specifically in codon 12, have been shown to be important for cancer progression and may predispose to more aggressive biological behavior in patients with advanced colorectal cancer [23]. Recently, BRAF (a member of the RAF kinase family) gene mutations, which result in a constitutively active MAP kinase cascade, have been identified in more than 60% of malignant melanomas [24]. Studies of primary tumor samples and cell lines have also shown constitutive activation or overactivation of the MAP kinase pathway in cancers of the pancreas, colon, lung, ovary, and kidney [25]. Thus, there is a strong correlation between cancers and an overactive MAP kinase pathway resulting from genetic mutations. Because activation of the RAS/RAF MAP kinase cascade plays a pivotal role in cell proliferation, inhibition of this pathway is believed to be beneficial in hyperproliferative diseases. It is anticipated that inhibition of MEK activity should inhibit transduction of the mitogenic signals from multiple pathways, resulting in an effect on tumor proliferation, differentiation, and survival. Inhibition of MEK has been shown to have potential therapeutic benefit in several studies [26, 27].
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2.1.3 mutations in the pi3k-akt-mtor

The phosphatidylinositol 3-kinase (PI3K) family of lipid kinases converts phosphatidylinositol-4,5-bisphosphate to phosphatidylinositol-3,4,5-trisphosphate, which initiates a signaling cascade that promotes cell growth, proliferation, motility, and survival [28]. PI3 kinases activate AKT. The PI3K-AKT pathway is downstream of the common growth factor receptor tyrosine kinases (RTKs), including EGFR, HER2, and IGFR, and is a likely driver of tumor progression in most carcinomas [29-31]. AKT promotes cell survival, growth, proliferation, migration; as well as angiogenesis and invasion by acting on multiple downstream pathways. AKT protein kinase is activated in a substantial proportion of human solid tumors, including breast, endometrial, ovarian, prostate, pancreatic, colon, gastric, and NSCLC. Upregulation of AKT can be caused by direct amplification/mutation of AKT, or by overexpression of RTKs, PI3K, and RAS, and/or by inactivation of the tumor suppressor PTEN [32, 33]. AKT activates and/or inhibits other proteins including BAD, FOXO, and mTOR [34]. Activation of AKT is an important mechanism of chemotherapy/radiotherapy resistance, and is therefore of great interest as a potential pathway to overcome resistance. Numerous references provide support for AKT inhibitors in the treatment of various malignancies [29-31, 35-65]. AKT phosphorylation as a pharmacodynamic (PD) marker has also been explored in early phase clinical trials [34]. Inactivation or hypoactivation of PTEN causes overactivation of the PI3K-AKT pathway [34]. PTEN inactivation is caused by a variety of mechanisms including somatic mutations, deletions, promoter methylation, and/or loss of heterozygosity. These changes are commonly found in many cancers including prostate cancer, endometrial cancer, and glioblastoma and are often associated with advanced disease stage. mTOR is a serine/threonine kinase that is structurally related to PI3K. When mTOR binds to other intracellular proteins; there are two distinct complexes formed known as mTORC1 and mTORC2 [34]. The currently approved mTOR inhibitors: rapamycin (sirolimus),
everolimus, and temsirolimus only block mTORC1. mTORC1 is made up of mTOR,
regulatory-associated protein of mTOR (raptor), and mLST8/GβL. Results from a recent Phase I study of doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies indicated that a high percentage of responders had PI3K aberrations [66].
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2.2 targeted genes/locus selection

Patients enrolled on study will have a tumor biopsy sequenced for one or more of the specific mutations of interest listed in Table 1. This sequencing may be performed prior to enrollment, to determine eligibility, or once the patient has started treatment, to confirm the results from previous CLIA sequencing. A minimum of two biopsy specimens will be shipped directly to the Laboratory of Molecular Characterization (MoCha), located at FNLCR. Biopsy samples (FFPE blocks) collected as part of another study or from a procedure performed due to medical necessity may be acceptable if the samples were collected within 6 months prior to registration on MPACT and the patient has not received any investigational or targeted treatment since that time. Upon receipt of specimens, a visual examination will be performed for acceptance. If all acceptance criteria are met, the specimen will be logged into the laboratory database for processing. Biopsy cores will 14 be processed and embedded in paraffin using routine histological procedures. A tissue section will be stained for histological examination for tumor content. Samples with a tumor content of at least 50% (with minimal necrosis and stromal tissue) will be subjected to nucleic acid extraction using Qiagen's AllPrep FFPET nucleic acid extraction methodology. Samples with tumor content less than 50% will undergo tumor enrichment (described below). Resultant DNA and RNA will be quantified by, but not limited to, NanoDrop spectroscopy. If sufficient DNA is obtained, 20 ng will be used for library preparation using a custom AmpliSeq kit, "MATCHv3" (until Amendment P, the assay used MPACTv2.0). This custom panel was designed and developed by MoCha to support this clinical study. The panel employs AmpliSeq multiplex PCR technology to amplify and prepare clinical specimens for sequencing of genetic loci (targets) used for therapy selection in this trial. The panel currently includes 13 DNA damage repair actionable genes (Table 1). The genes were selected using several criteria:
- Genes within the DNA damage repair pathway were selected based on demonstrating a minimum frequency (5%) of somatic variants as listed in the COSMIC [catalogue of somatic mutation in cancer] database1 version \#86.  
- Additional genes were added, including the targets of the study drugs.  
- The Molecular Tumor Board further assessed the genes selected and agreed upon a final reportable variant protocol based on reported frequency as well as preclinical and clinical literature associated with a given gene and its variant.  
All sequencing will be performed in a Clinical Laboratory Improvement Amendments (CLIA)- certified laboratory. All of the DNA damage repair genes covered by the panel are tumor suppressor genes and will be assessed for loss of function mutations (Table 1). These loss of function mutations have been previously reported in the COSMIC database (version 86) or ClinVar. In addition to the hotspot aMOIs, the panel will also report on novel loss of function mutations that create a frameshift of premature stop codon in the predicted protein. The sequencing data for these genes will be shared with the patient (Appendix H) once the results are available. Targeted analysis will not include analyzing for known mutations in receptor tyrosine kinases or TP53. The clinical specimen will be sequenced using the Ion Torrent Personal Genome Machine. A variety of specimen and assay quality checks are built into the assay process and detailed in the SOPs. MoCha has prepared an analytical validation plan with assay performance testing, validation, and quality control metrics. These metrics include DNA yield and quality, minimum percentage tumor nuclei per specimen, read depth, and positive and negative controls (see summary below) to ensure valid assay performance and result reporting.  
| Gene Name   | Pathways/Function   | Gain or Loss of Function?   |
|-------------|---------------------|-----------------------------|
| ATM         | DNA repair pathway  | Loss                        |
| NBN         | DNA repair pathway  | Loss                        |
| RAD51       | DNA repair pathway  | Loss                        |
| RAD51B      | DNA repair pathway  | Loss                        |
| RAD51C      | DNA repair pathway  | Loss                        |
| RAD51D      | DNA repair pathway  | Loss                        |
| PALB2       | DNA repair pathway  | Loss                        |
| BRCA1       | DNA repair pathway  | Loss                        |
| BRCA2       | DNA repair pathway  | Loss                        |
| CHEK1       | DNA repair pathway  | Loss                        |
| CHEK2       | DNA repair pathway  | Loss                        |
| FANCA       | DNA repair pathway  | Loss                        |
| MRE11A      | DNA repair pathway  | Loss                        |
| IDH1        | DNA repair pathway  | Loss                        |
| IDH2        | DNA repair pathway  | Loss                        |  
Table 1. Genes and Pathways of Interest (DNA repair genes only after Amendment U)  
| Quality Metrics         | Threshold                                                   |
|-------------------------|-------------------------------------------------------------|
| Tissue Specimen Review  | >50% non-necrotic tumor nuclei present in section           |
| DNA Recovery            | > 20 ng                                                     |
| Library Yield           | > 10 pM                                                     |
| Testing Fragments       | TF-A/D > 80% AQ17, Read Length Histogram >90 bp             |
| Reads per Sample        | >350,000                                                    |
| Amplicon Coverage       | > 80% of amplicons coverage >450x                           |
| Positive (CPSC) Control | Detect and call all plasmid variants                        |
| Negative Control CEPH   | Detect no false-positive aMOIs                              |
| LibNTC Sequence Data    | Total reads < 2% read libraries OR <120 bp mean read length |  
After a clinical specimen has completed sequencing and passed all quality checks and filters, the data will be analyzed. The report will be reviewed (by investigators indicated with an F on the cover page) and treatment assignments made based on the locked down algorithm defined in the protocol. All delinked RNA and DNA will be stored under appropriate conditions until further sample studies are indicated. Delinking of patient identifiers will be performed in a secure manner prior to use performing, but not limited to, whole exome sequencing and circulating tumor DNA (ctDNA) for research purposes. Mutations will be reported based on their presence in tumor cells and the percent of cells demonstrating the predefined mutation. An adequate tumor biopsy sample will contain at least 50% tumor with minimal necrosis and stromal tissue; samples with less than 50% tumor will be reflexed for tumor enrichment using a standardized macrodissection protocol. In case of samples with insufficient tumor content or DNA yield, 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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2.3 study agents

Proprietary information about each of the study agents is included in this protocol document as an appendix. Veliparib will be administered with temozolomide.
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2.3.1 veliparib

Veliparib is an orally available, small molecule inhibitor of PARP. Preclinical and clinical data show that inhibition of PARP potentiates the effects of DNA-damaging chemotherapeutic drugs such as the alkylating agent temozolomide [67]. In this study, Veliparib and temozolomide will be administered to patients with defects in DNA repair pathways. Please refer to Appendix I for more information.
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2.3.2 temozolomide

Temozolomide is an oral alkylating agent approved by the FDA for the treatment of certain cancerous tumors in the brain of adult patients. Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, 3-methyl-(triazen-1-yl)imidazole-4carboxamide (MTIC). MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) which is known to be an intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which is believed to be the active alkylating species.
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2.3.3 trametinib dimethyl sulfoxide (gsk1120212)

Trametinib DMSO is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 activation and kinase activity. The safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles, and activity of trametinib DMSO are currently being evaluated in 13 ongoing monotherapy and combination therapy clinical trials involving subjects with a variety of cancers. Trametinib DMSO was recently approved for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E or BRAFV600K mutations based on a statistically significant prolongation of progression free survival over chemotherapy (4.8 months vs. 1.5 months) in 322 patients on a randomized active-control trial.
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2.3.4 azd1775 (this arm was

AZD1775 is a selective, adenosine-triphosphate (ATP) competitive, small molecule inhibitor of Wee1 kinase that directly inhibits phosphorylation of CDC2. In vitro experiments have demonstrated that AZD1775 has synergistic antitumor effects when administered in combination with various DNA damaging agents that have divergent mechanisms of action. In this study, AZD1775 will be administered with carboplatin. Results from preclinical and clinical studies suggest that the combination of AZD1775 with carboplatin has antitumor efficacy and is well tolerated; refer to Appendix J for more information. 2.3.5 **Carboplatin** (*This arm was closed to new accrual with Amendment U*) The alkylating agent carboplatin acts by binding DNA to form interstrand DNA crosslinks that interrupt cell division. It is approved by the FDA for the treatment of patients with ovarian cancer and non-small cell lung cancer, and is also used for the treatment of patients with small cell lung cancer, head and neck cancer, endometrial cancer, metastatic seminoma, and breast cancer. Carboplatin is eliminated by renal excretion; clearance is related to the glomerular filtration rate (GFR), therefore the drug is dosed based on the GFR and the target area under the concentration versus time curve (AUC). The main side effects of carboplatin are myelosuppression, nausea, vomiting, renal toxicity, and neurotoxicity. 2.3.6 **Everolimus** (*This arm was closed to new accrual with Amendment U*) The mTOR inhibitor everolimus was approved by the FDA for patients with advanced renal cell carcinoma (RCC) based on results from a multicenter, randomized, doubleblind Phase III trial comparing everolimus (10 mg daily) and placebo in 416 patients with metastatic RCC whose disease had progressed despite prior treatment with vascular endothelial growth factor-targeted therapy (sunitinib, sorafenib, or both sequentially) [68, 69]. Median progression-free survival was 4.9 months in the everolimus arm and 1.9 months in the placebo arm; objective response rates were 2% and 0%, respectively. As described in Section 2.1.3, the serine-threonine kinase mTOR is an essential component of the multiprotein mTOR complex 1 (mTORC1), along with regulatory-associated protein of mTOR (raptor). Once activated through PI3K activation of AKT, mTORC1 functions as a key regulator of cell growth by phosphorylating 4E-binding protein 1 (4EBP1) and p70S6K (S6K), translation initiation factors required for protein synthesis [70, 71]. Everolimus binds to the intracellular protein, FKBP-12, which in turn binds mTOR, impairing its activity and inhibiting translation of proteins essential for cell cycle progression and survival. The main side effects of everolimus reported in patients with RCC are stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The recommended dose of everolimus for the treatment of patients with advanced RCC is 10 mg, to be taken once daily; this dose will be administered on this trial.
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2.4 study disease

Patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy and/or there are no standard therapies available that are known to prolong survival will be enrolled on study and undergo mandatory tumor biopsy. This tumor biopsy will be sequenced for presence of specific mutations of interest in a CLIA-certified laboratory. The following specific mutations in pathways will be assessed:
1. Mutations in DNA repair pathways 2. Mutations in the PI3K pathway (Not currently accruing) 3. Mutations in the RAS/RAF/MEK pathway (Not currently accruing)
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2.5 genetic sequencing research ethics

This trial will collect identifiable genetic data from all patients enrolled to determine whether or not their tumors have a mutation(s) in one or more of the pathway of interest. We will screen for pre-defined variations in genes in a CLIA-certified laboratory for assignment of patient treatment on study. As treatment options and data analyses will be based on this information, deidentifying the samples is not feasible. Designing the study therefore poses challenging 18 questions about informed consent, the privacy of the patient and the patient's family, the researchers' obligation to disclose genetic information to the patient, and the use and storage of research data, as well as of the selection and interpretation of gene variants [72-74]. In the vast majority of cases we do not know the medical significance of genetic variants [75, 76]. These challenges will continue to be evaluated to maintain the rigor and integrity of the study and the wellbeing of our patients. A Certificate of Confidentiality has been obtained from the NIH to help protect the privacy of all study participants. The protocol includes separate informed consent forms for the screening biopsy and treatment parts of the study; each patient will know whether or not their tumor has a variation in a gene of interest. Patients with actionable mutations that may establish eligibility for other clinical trials or targeted agents, including MATCH (*Targeted Therapy Directed by Genetic Testing in* Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma, NCT02465060), which uses the same custom AmpliSeq screening panel as MPACT, will be informed that they may have other treatment options. Information on tumor gene variants that form the basis of treatment assignment will be stored in the patient's medical records. Whole exome sequencing (performed for research purposes) of tumor and blood can detect nonambiguous germline variants, which may raise health and privacy implications for the patient and his or her family. Whole exome sequencing will not be validated for clinical use and no clinical decisions can be made based on its results. In addition, given the uncertain clinical significance of some of these variants and the ethical implications, we will perform such research analysis on de-identified samples only. Once each patient has completed treatment on study and is taken off study, patient identifiers will be de-linked and we will perform whole exome sequencing on the de-identified samples. No genetic data will be shared with the patient other than the data from the targeted sequencing panel. All other analysis will be performed on deidentified samples. The process for de-identifying the samples is described in Section 9.4.1.  
This study affords a unique opportunity to collect information about the prevalence of mutations in genes associated with cancer, as well as how patients' tumors respond to targeted therapy in the refractory tumor setting; DNA variants and changes in RNA expression from tumors collected when patients progress on study drugs is anticipated to illuminate resistance mechanisms that will inform subsequent studies and improve patient outcomes.
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2.5.1 nih genomic data sharing

The NIH Genomic Data Sharing (GDS) Policy ensures broad and responsible sharing of genomic research data from all NIH-funded research2. Providing that patient consent has been obtained, whole-exome sequencing data generated for research purposes from samples unlinked from patient identifiers will be submitted to the Database of Genotypes and Phenotypes (dbGaP) for controlled-access use within a time frame consistent with study CRADAs and data publication. The identities of research participants will not be disclosed to dbGaP or to secondary users of the data. Genomic data generated from patients before this trial became a multicenter study will not be subject to GDS policy as adequate consent was not obtained from these individuals.
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2.6 rationale for the study

The original proposal was designed to address, in a randomized trial, whether patients with underlying mutations in a given pathway in their tumor are more likely to derive clinical benefit if treated with agents that target that pathway than if treated with agents that do not, as well as to address this question, in a non-randomized fashion, for each separate cohort defined by mutation status. Randomization was taken out of the study design with Amendment U. Patients will receive one of the agents/regimens defined to work on one of their identified mutations. In the absence of a randomized control arm, the performance of each individual mutational status cohort will be compared to that of historical controls. If no objective responses are observed among the initial 12 patients of a 30-patient Arm A agent cohort, the cohort will be terminated early. An optional tumor biopsy will be performed at the time of disease progression to assess for new acquired mutations; this biopsy may, if feasible, 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. The treatment regimens and number of treatment regimens may change over time as long as the same set of regimens is offered to a given set of patients. The doses that will be administered are Phase II-recommended doses.
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2.6.1 veliparib plus temozolomide arm

As of Amendment U, this is the only arm open to accrual. *Seven patients had been* assigned to this arm prior to the study being placed on hold for futility analysis (targeted plus control arms). The combination of veliparib with temozolomide in patients with DNA damage mutations is supported by preclinical data in patient-derived xenograft (PDX) mouse models. Overall, 32 PDX models have been treated with this combination; 8 have demonstrated delayed tumor growth (unpublished data). Complete or partial response, as well as an increase in relative median event-free survival, has been observed with veliparib plus temozolomide in tumors with a range of DNA damage mutations. Based on these data, we have revised the list of actionable mutations of interest for the veliparib plus temozolomide arm. We expect that the new eligibility criteria, including variants in DNA repair genes BRCA1, BRCA2, CHK2, and ATM, will allow more patients with potential to benefit from this combination to enroll on this treatment arm.
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3. patient selection (tumor sequencing/drug

Patients meeting the criteria defined below will be enrolled on study, then undergo a tumor biopsy. The tumor will be sequenced for specific mutations of interest defined in Section 2.2; only if such mutations are detected will the patient continue on study to the randomization/treatment part of this protocol. The eligibility criteria for both the tumor sequencing and treatment parts of this protocol are similar, such that in general, a patient eligible for tumor sequencing will be eligible for the subsequent treatment part of the protocol if his/her tumor contains a mutation of interest. **Additional agent-specific** treatment exclusions are listed in Section 3.4; agent-specific exclusions are to ensure patient safety.
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3.1 eligibility criteria tumor biopsy

3.1.1 Patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy and/or no standard of treatment exists that has been shown to prolong survival.  
3.1.2 Patient must have tumor amenable to percutaneous or excisional skin biopsy and be willing to undergo a tumor biopsy, or Biopsy samples (FFPE blocks) collected on another study or from a procedure performed due to medical necessity may be acceptable if collected within 6 months prior to registration on MPACT and providing that the patient has not received any investigational or targeted treatment since that time, or A report from an MATCH study designated CLIA laboratory (see https://ecogacrin.org/nci-match-eay131-designated-labs) that a patient has a variant in the genes of interest.  
3.1.3 Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan.  
3.1.4 Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment, denosumab, or similar agents are eligible to participate and may continue this treatment. Patients with prostate cancer may continue LHRH agonists or antagonists.
3.1.5 Age ≥ 18 years. Children are excluded from this study, but may be eligible for future pediatric trials.  
3.1.6 Karnofsky performance status ≥ 70%, see Appendix A. 3.1.7 Life expectancy > 3 months. 3.1.8 Patients must have adequate organ and marrow function as defined below:  
| − absolute neutrophil count   | ≥1,000/L (mcL)                             |
|-------------------------------|---------------------------------------------|
| − platelets                   | ≥100,000L (mcL)                           |
| − total bilirubin             | < 1.5 X institutional upper limit of normal |
| − AST(SGOT)/ALT(SGPT)         | ≤ 3 X institutional upper limit of normal   |
| − creatinine                  | < 1.5 X institutional upper limit of normal |
| OR                            |                                             |  
− creatinine clearance ≥ 60 mL/min for patients with creatinine levels ≥1.5 X institutional upper limit of normal.  
3.1.9 The effects of these targeted agents on the developing human fetus are unknown or anticipated to cause fetal harm based on their mechanism of action. For this reason, women of childbearing potential and men must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for 3 months after completion of study. Because there may be a risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug.  
3.1.10 Patients with history of CNS metastases who have received treatment and who either have not had seizures or have been on stable doses of anti-seizure medicine and had no seizures for 4 weeks will be eligible. Enzyme-inducing anticonvulsants are contraindicated.  
3.1.11 Ability to understand and the willingness to sign a written informed consent document (subjects with impaired decision-making capacity are not eligible).
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3.2 exclusion criteria tumor biopsy

3.2.1 Women who are pregnant or breastfeeding. 3.2.2 Patients who are receiving any other investigational agents. Patients on other trials will be eligible as long as they are no longer receiving study treatment.  
3.2.3 Patients with uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months, invasive fungal infections, or active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e., quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCVRNA) are not eligible to participate. Testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated.  
3.2.4 Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with Crohn's disease or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow tablets or capsules whole. Tablets or capsules must not be crushed or chewed; nasogastric or G-tube administration is not allowed.  
3.2.5 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions.
3.2.6 Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic use.  
3.2.7 Patients who have previously been treated with the combination of temozolomide plus a PARP inhibitor should not be considered eligible for a biopsy given that these patients would not be eligible for the active Veliparib plus temozolomide arm.
Patients who meet the screening criteria and have a tumor biopsy determined to have one of the specific mutations of interest (defined in Section 2.2) will be eligible to participate in the treatment part of this protocol. If the patient does not meet the criteria in Section 3.3 **or the patient has any of the conditions listed in Section 3.4, the patient is not** eligible for this trial.
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3.3 eligibility criteria targeted treatment

3.3.1 Patient must have predefined targeted mutation in tumor biopsy as defined in Section 2.2.  
3.3.2 Patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy or for which no standard therapy exists that has been shown to prolong survival.
3.3.3 Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan.  
3.3.4 Any prior therapy, radiotherapy, or major surgery must have been completed
≥ 3 weeks (> 6 weeks for nitrosoureas or mitomycin C) or 5 half-lives of the agent
(whichever is shorter) prior to enrollment on protocol, and the participant must have recovered to eligibility levels from prior toxicity. RFA of localized lesions should have been performed ≥ 2 weeks prior to starting treatment.  
3.3.5 Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment, denosumab, or similar agents are eligible to participate and may continue this treatment. Patients with prostate cancer may continue LHRH agonists or antagonists.
3.3.6 Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of study investigational agents in patients < 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.  
3.3.7 Karnofsky performance status ≥ 70%, see Appendix A.
3.3.8 Adequate organ and marrow function as defined in Section 3.1.8
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3.3.9 life expectancy > 3

3.3.10 The effects of these targeted agents on the developing human fetus are unknown or anticipated to cause fetal harm based on their mechanism of action. For this reason, women of childbearing potential and men must agree to use highly effective contraception (see list below) prior to study entry, for the duration of study participation, and for 3 months after completion of study.  
Total abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception). Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). (For female subjects on the study, the vasectomised male partner should be the sole partner for that subject). Use of a combination of any two of the following (a+b or a+c or b+c):
a.Use of oral, injected, implanted or other hormonal methods of contraception b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository In case of use of oral contraception, women should have been stable on the oral agent before taking study treatment. Sexually active males must use a condom during intercourse 3.3.11 Because there may be a risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug.  
3.3.12 Patients with ovarian cancer or metastatic breast cancer and BRCA mutations must have received approved PARP inhibitor therapy; these patients are eligible for the Veliparib plus temozolomide arm unless the PARP inhibitor was administered with temozolomide.  
3.3.13 Patients with a history of seizures are not eligible to receive Veliparib, 3.3.14 Patients who have had prior treatment with any PARP inhibitor in combination with temozolomide are not eligible to receive treatment with Veliparib on this study. Patients who have received prior temozolomide or PARP inhibitor with or without other chemotherapy/targeted agent should not be excluded.  
3.3.15 Patients must have ≥10.0 g/dL Hb and no blood transfusion in the past 28 days to
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3.4 exclusion criteria targeted treatment

3.4.1 Women who are pregnant or breastfeeding. 3.4.2 Patients who are receiving any other investigational agents. Patients on other trials will be eligible as long as they are no longer receiving study treatment.  
3.4.3 Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients who have a history of seizures are not eligible to receive Veliparib 3.4.4 Patients with uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months, invasive fungal infections, or active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e., quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCVRNA) are not eligible to participate. Testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated.  
3.4.5 Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with Crohn's disease or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow tablets or capsules whole. Tablets or capsules must not be crushed or chewed; nasogastric or G-tube administration is not allowed.  
3.4.6 HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions.  
3.4.7 Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics (i.e., CYP450, PgP) of any of the study drugs will be determined following review of their cases by the PI. Patients on strong and moderate cytochrome P450 system inducers or inhibitors (Appendix B) are ineligible. Every effort would be made to switch patients off medications that are known substrates of CYP450; if it is medically important for the patient to remain on such medications, these patients can still be eligible to participate based on PI discretion. Refer to Section 8 for more detailed information.  
3.4.8 Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic use.  
3.4.9 Patients who have a history of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for > 3 years.  
3.4.10 Patients with treatment-related AML (t-AML)/MDS, or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive Veliparib due to reports of MDS and leukemia secondary to oncology therapy on CTEP-sponsored studies utilizing Veliparib.
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3.5 evaluation for enrollment for

3.5.1 Histologic confirmation of solid malignancy. 3.5.2 History and physical examination: Complete history and physical examination
(including height, weight, vital signs, performance score, EKG) will be conducted within 8 days prior to enrollment.  
3.5.3 Imaging Studies (Baseline): Imaging studies to determine biopsiable disease. 3.5.4 Laboratory Evaluation: Baseline laboratory data are to be obtained within 8 days prior to enrollment (fasting blood preferred):
- Hematological Profile: CBC with differential
- Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN,
calcium, creatinine, glucose, phosphorus, total protein, SGOT[AST], SGPT[ALT], magnesium, potassium, and sodium
- Serum or urine pregnancy test for female participants of childbearing potential
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3.6 evaluation for treatment on

3.6.1 History and physical examination: complete history and physical examination
(including weight, vital signs, performance score, EKG) will be conducted within 8 days prior to enrollment. If the patient's condition deteriorates prior to initiation of treatment, evaluations should be repeated within 48 hours prior to initiating treatment.  
3.6.2 Imaging Studies (Baseline): Every participant should have an evaluation of known sites of disease as part of the baseline evaluation. All patients will be required to undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of disease within 28 days prior to starting study drugs. MRI or CT scan with contrast of the brain, MRI liver, MRI for other disease sites, ECHO/MUGA or bone scan may be done as clinically indicated before starting study drugs (ECHO/ MUGA required for patients receiving trametinib or everolimus).  
3.6.3 Laboratory Evaluation: Baseline laboratory data are to be obtained within 8 days prior to enrollment and within 3 days prior to starting study drugs. If the patient's condition deteriorates prior to initiation of treatment, laboratory evaluations should be repeated within 48 hours prior to initiating treatment:
26  
a. Hematological Profile: CBC with differential. b. Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN,
calcium, creatinine, glucose, phosphorus, total protein, SGOT[AST],
SGPT[ALT], magnesium, potassium, and sodium.  
c. Serum or urine pregnancy test for female participants of childbearing potential.
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4. registration procedures 4.1 investigator

Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all individuals contributing to NCI-sponsored trials to register and to renew their registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP)
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE
or acting as a primary site contact) must complete their annual registration using CTEP's webbased Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  
Documentation requirements per registration type are outlined in the table below.  
| Documentation Required                                                       | IVR   | NPIVR   | AP   | A   |
|------------------------------------------------------------------------------|-------|---------|------|-----|
| FDA Form 1572                                                                | ✔     | ✔       |      |     |
| Financial Disclosure Form                                                    | ✔     | ✔       | ✔    |     |
| NCI Biosketch (education, training,  employment, license, and certification) | ✔     | ✔       | ✔    |     |
| HSP/GCP training                                                             | ✔     | ✔       | ✔    |     |
| Agent Shipment Form (if applicable)                                          | ✔     |         |      |     |
| CV (optional)                                                                | ✔     | ✔       | ✔    |     |  
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications. In addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the following:  
- Added to a site roster - Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN - Act as the site-protocol PI on the IRB approval
Additional information can be found on the CTEP website at https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov.
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4.2 site registration

This study is supported by the NCI Cancer Trials Support Unit (CTSU). Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can be approved to enroll patients. Assignment of site registration status in the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory criteria including but not limited to the following:
- An active Federal Wide Assurance (FWA) number
- An active roster affiliation with the Lead Network or a participating organization
- A valid IRB approval - Compliance with all protocol specific requirements.  
In addition, the site-protocol PI must meet the following criteria:  
- Active registration status - The IRB number of the site IRB of record listed on their Form FDA 1572 - An active status on a participating roster at the registering site
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally. The CIRB's approval of the SSW is then communicated to the CTSU Regulatory Office. For the SSW approval to be processed, the Signatory Institution must inform the CTSU which CIRBapproved institutions aligned with the Signatory Institution are participating in the study.  
Downloading Regulatory Documents Site registration forms may be downloaded from the *9149* protocol page located on the CTSU Web site. Permission to view and download this protocol is restricted and is based on person and site roster data housed in the CTSU RSS. To participate, Investigators and Associates must be associated with the Corresponding or Participating protocol organization in the RSS.  
- Go to https://www.ctsu.org and log in using your CTEP IAM username and password.  
- Click on the Protocols tab in the upper left of your screen. - Either enter the protocol \# in the search field at the top of the protocol tree, or
- Click on the By Lead Organization folder to expand, and then select *LAO-NCI*,
and protocol \#9149.  
- Click on LPO Documents, select the Site Registration documents link, and download and complete the forms provided. (Note: For sites under the CIRB initiative, IRB data will load to RSS as described above.)
Requirements for 9149 Site Registration:
- IRB approval (For sites not participating via the NCI CIRB; local IRB
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted)
- Local informed consent document Submitting Regulatory Documents Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal: www.ctsu.org (members' area) → Regulatory Tab →
Regulatory Submission When applicable, original documents should be mailed to: CTSU Regulatory Office 1818 Market Street, Suite 3000, Philadelphia, PA 19103 Institutions with patients waiting that are unable to use the Portal should alert the CTSU
Regulatory Office immediately at 1-866-651-2878 to receive further instruction and support.
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checking site registration status

You can verify your site registration status on the members' section of the CTSU website.  
- Go to https://www.ctsu.org and log in to the members' area using your CTEPIAM username and password
- Click on the Regulatory tab at the top of your screen - Click on the Site Registration tab - Enter your 5-character CTEP Institution Code and click on Go
Note: The status given only reflects compliance with IRB documentation and institutional compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect compliance with protocol requirements for individuals participating on the protocol or the enrolling investigator's status with the NCI or their affiliated networks.
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4.2.1 open / iwrs

Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). OPEN is a web-based registration system available to users on a 24/7 basis. It is integrated with the CTSU Enterprise System for regulatory and roster data interchange and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient registration/randomization assignment. Patient enrollment data entered by Registrars in OPEN / IWRS will automatically transfer to the NCI's clinical data management system, Medidata Rave. As this trial has a slot reservation requirement, OPEN will connect to IWRS at enrollment initiation to check slot availability. Registration staff should ensure that a slot is available and secured for the patient before completing an enrollment. Slots can be reserved for a maximum of 14 calendar days. The OPEN system will provide the site with a printable confirmation of registration and treatment information. Please print this confirmation for your records.
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open/iwrs user requirements

OPEN/IWRS users must meet the following requirements:
- Have a valid CTEP-IAM account (i.e., CTEP username and password). - To enroll patients or request slot reservations: Be on an ETCTN Corresponding or Participating Organization roster with the role of Registrar. Registrars must hold a minimum of an AP registration type.  
- To approve slot reservations or access cohort management: Be identified to Theradex as the "Client Admin" for the study.  
- Have regulatory approval for the conduct of the study at their site.  
Prior to accessing OPEN/IWRS, site staff should verify the following:
- All eligibility criteria have been met within the protocol stated timeframes.  
- If applicable, all patients have signed an appropriate consent form and HIPAA
authorization form.
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open/iwrs questions?

Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. Theradex has developed a Slot Reservations and Cohort Management User Guide, which is available on the Theradex website: website http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11 This link to the Theradex website is also on the CTSU website OPEN tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7862 or Theradex main number 609-799-7580; CTMSSupport@theradex.com.
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4.3 general guidelines

Following registration, patients should be assigned to protocol treatment as specified in Section 5.1. Issues that would cause treatment delays should be discussed with the Principal Investigator. If a patient does not receive protocol therapy following registration, the patient's registration on the study may be canceled. The Study Coordinator should be notified of cancellations as soon as possible. Please make every effort not to schedule biopsy collections on a Friday as FNLCR cannot accept courier deliveries at weekends.
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4.4 randomization procedures (n/a) 5.

After signing the consent form and enrolling on the study, patients will undergo mandatory tumor biopsy as described in Section 9 unless a CLIA-certified tumor mutation report from an MATCH study designated lab (see https://ecog-acrin.org/nci-match-eay131-designated-labs) indicating a study aMOI is provided. Reports from other academic, clinical, or commercial testing organizations will not be accepted due to the level of evidence needed for this research protocol. Genetic sequencing at the NCI will be performed in the CLIA-certified laboratory of Dr. Mickey Williams, Director, Molecular Characterization and Clinical Assay Development Laboratory (MoCha), to assess for the presence of specific, pre-defined mutations of interest. The laboratory will return notification of whether a mutation of interest has been detected in approximately 2 weeks, including details about the specific mutation/pathway for assignment to the treatment arm based on predefined criteria. Patients in whom mutations of interest are not detected will be taken off study. Patients considered eligible for the study due to results from a MATCH-designated lab will have a biopsy collected during cycle 1 for confirmatory testing with the MPACT Oncominev3 assay; patients who do not have their actionable mutation confirmed can choose to continue treatment but will not count towards evaluable patients and will be replaced for futility analysis. All treatment will be open-label in this trial. Drugs will be administered at the recommended Phase II doses and schedules. A new cycle may begin 1 day earlier or 1 day later than it would otherwise be scheduled to allow for flexibility for days the clinic is closed and other unexpected events. CT scans will be performed at baseline, and repeat imaging scans will be performed every 2 cycles (8 weeks for 28-day schedules, 6 weeks for 21-day schedules). Once a patient has been on a treatment for more than 1 year, the CT scans will be performed every 3 cycles for 28day cycles or every 4 cycles for 21-day cycles. History and physical exam, labs (CBC with differential; serum chemistries, including fasting glucose) will be performed at the start of each cycle (within 3 days prior to start of new cycles). Additional evaluations will be conducted as clinically indicated at the investigator's discretion, or more frequently for patients on certain treatment arms as specified in Section 10. Lipid monitoring (triglycerides and cholesterol) will be performed at restaging (every 2 cycles or as defined above) and urinary protein the start of each cycle for patients on everolimus only. Patients will be asked to maintain a Study Medication Diary (Appendix D) and record each dose of medication. Patients will be given instructions for completing the medication diary and will be asked to return it to the clinic staff at the end of each cycle. All patients will be carefully monitored for side effects while on study. Appropriate dose modifications are described in Section 6.
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5.2 targeted therapy arms

Treatment assignment is made by GeneMed, an informatics system that performs treatment assignments based on the locked down algorithm defined in the protocol. The assignment will be sent to the treating physician once it is verified within 24-48 hours. The treating physician and the patient will not be blinded to the sequencing data. Patients with tumor mutations of interest will receive an agent prospectively identified to work on that mutation/pathway (see below). As long as the same set of protocols are offered to a given set of patients, the number and actual treatments regimens can vary over time. At the time of Amendment Y, the last patient randomized to the Trametinib DMSO cohort under the original study design remains on treatment with the option that she and/or her physician may now be informed prior to, rather than at, disease progression about her mutational status and arm assignment. The study team would also be informed. The patient, in discussion with the treating physician, may still crossover to a study treatment prospectively identified to work on the identified mutation/pathway per the original study design (see list below). The patient may not switch to another treatment and then back to Trametinib DMSO. The treatment regimens are as follows:  
- Veliparib plus temozolomide for defects in DNA repair pathways - AZD1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathways *(no* longer an active study drug as of March 2018)
- Everolimus (mTOR inhibitor) for mutations in the PI3K pathway (no longer an active study drug as of March 2018)
- Trametinib DMSO (MEK inhibitor) for mutations in the RAS/RAF/MEK pathway *(no* longer an active study drug as of March 2018)
Treatment exceptions are also listed in Section 3.3. The following patients will **not** receive certain treatments on this protocol:
1) Patients with ovarian cancer and BRCA mutations must have received specific PARP
inhibitor therapy.  
2) Patients with treatment-related AML (t-AML)/MDS, or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive Veliparib due to reports of MDS and leukemia secondary to oncology therapy on CTEP-sponsored studies utilizing Veliparib. Information on whether a mutation(s) of interest was detected for a given patient as well as what drugs are allowed for assignment of a treatment regimen will be provided to the study team; the Biopsy Sequencing Results and Analysis Form (Appendix F) will be provided to the clinician. Arm A: Targeted treatment based on the detected genetic mutation **will be assigned.** Mutations will be reported based on their presence in tumor cells and the percent of cells demonstrating the pre-defined mutation (as allele frequency). At the time of disease progression for all targeted therapy patients, an optional tumor biopsy may be collected to assess for new acquired mutations; 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. No more than 3 tumor biopsy procedures will be performed: one mandatory at baseline, one optional repeat biopsy if sufficient tumor DNA cannot be isolated at baseline, and one optional biopsy at or near time of disease progression to assess for new acquired mutations.
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5.3 agent administration 5.3.1 veliparib

The Veliparib dose of 40 mg BID on days 1-7 with temozolomide administered 150 mg/m2 po QD days 1-5 in 28-day cycles was selected based on clinical results presented at ASCO [77] [78]. The dose of temozolomide is based on BSA then rounded off to the nearest 5 mg. Patients who receive temozolomide will have an evaluation of their LFTs at the time of coming off-treatment.
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5.3.2 everolimus

Everolimus will be administered once a day at a dose of 10 mg each day in 28-day cycles. Tablets should not be crushed or chewed and should be swallowed whole with a glass of water. If patients miss a dose of everolimus, they may still take it up to 6 hours after the time they would normally take it. If more than 6 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take everolimus at the usual time; patients should not take 2 doses to make up for the one that they missed. If vomiting occurs, no attempt should be made to replace the vomited dose. Caregivers should be advised to wash their hands thoroughly after touching the tablets. Patients on everolimus should also avoid close contact with others who have received live, attenuated vaccines (e.g., intranasal influenza).
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5.3.3 trametinib dmso

Trametinib DMSO will be administered at 2 mg each day in 28-day cycles. Drug must be taken while fasting (water is permitted) 1 hour before or 2 hours after a meal.
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5.4 general concomitant medication and

All patients will be provided with the best available supportive care. All concurrent medications should be documented prior to initiation of treatment and be periodically reviewed with the patient. Particular attention must be paid to medications which may prolong the QTc interval
(Appendix C) and agents that interact with CYP450 isoenzymes or are PgP inhibitors (Appendix B). Nausea/Vomiting: Nausea and vomiting will be considered refractory if they do not resolve to ≤ Grade 1 with treatment with a combination of at least 2 antiemetics. Concomitant treatment with aprepitant is not allowed for patients receiving AZD1775 because of potential drug-drug interaction.  
Diarrhea: If diarrhea develops and does not have an identifiable cause other than study drug administration, loperamide 4 mg po will be given after the first unformed stool with 2 mg po every 2 hours as long as unformed stools continue (4 mg every 4 hours while asleep). This regimen can be repeated for each diarrheal episode. Diarrhea will be considered refractory if it does not resolve within 24 hours to ≤ Grade 1 with the above regimen (total of 16 mg of loperamide a day). If the patient develops blood or mucus in the stool, dehydration, or hemodynamic instability, or fever along with the diarrhea, loperamide will be discontinued and the patient will be treated with IV fluids and antibiotics as medically indicated. Seizures: Seizures were seen in some animal toxicology studies with Veliparib, although at doses much higher than those anticipated for this study. Seizures in animals were successfully treated with lorazepam. Therefore, lorazepam should be considered as a possible first choice for controlling seizures, should they occur on this study. All patients experiencing a seizure on study need to be evaluated (e.g., imaging of the brain) to determine the cause. Anemia: Symptomatic anemia should be treated with red blood cell transfusion and is recommended if the hemoglobin falls below 8 mg/dL. Use of erythropoietin is allowed per accepted guidelines. Thrombocytopenia: Thrombocytopenia will be treated conservatively. In the absence of bleeding, fever, or a necessary invasive procedure, platelet transfusions should be given for a platelet count below 10,000/µL (mcL). If the patient is febrile, platelet transfusions should be given for a platelet count below 20,000/µL (mcL). If an invasive procedure is planned or the patient develops bleeding, platelet transfusions should be administered in accordance with standard of practice, usually maintaining a platelet count above 50,000/µL (mcL). Neutropenia: Febrile neutropenia is a life-threatening complication requiring hospitalization and urgent broad-spectrum antibiotics, as well as an aggressive search for the source and microbial cause of the episode. If clinically indicated,filgastrim may be initiated for Grade 4 neutropenia at the study investigator's discretion. Study medications will not be reinitiated until at least 24 hours after filgastrim administration. Reflux/Gastritis: Antacids and other anti-ulcer medications such as histamine H2-receptor antagonists may be used if clinically indicated. To avoid significantly altering gastric pH, when needed, these medications should be used 4 hours after study drug administration.  
Skin Rash: Appropriate clinical management of skin rash may be utilized as clinically indicated. Patients will be allowed to use topical emollients, topical steroids, antihistamine agents, and topical or oral antibiotics. A suggested step-wise approach follows:
- Grade 1 rash: Start with topical steroids (e.g., hydrocortisone, triamcinolone acetonide),
topical antibiotics such as clindamycin gel, or no treatment if the patient is asymptomatic. Use of topical steroid cream with higher potency or oral antibiotic may be considered early in patients with moderate rash on the face.  
- Grade 2 rash: Topical steroid cream, consider addition of an oral antibiotic (e.g.,
minocycline 100 mg PO BID) or a similar agent.  
- Grade 3 rash that does not respond to our measures: Dose interruption and/or dose reduction, in addition to supportive care as above.  
- Pruritus of any grade may be treated with an antihistamine, such as diphenhydramine or hydroxyzine hydrochloride.  
- Xerosis can be treated with classical emollients.
Hyperglycemia: Blood glucose home monitoring will be initiated in patients with persistently elevated fasting glucose (> 160 mg/dL, CTCAE Grade ≥ 2). Appropriate clinical management including oral anti-hyperglycemic medication or insulin, and supportive care (e.g., electrolyte management and hydration) will be provided as clinically indicated.
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5.5 definition of off-study parameters

In the absence of treatment delays due to adverse events, treatment may continue per protocol until one of the following criteria applies:
- Disease progression - Intercurrent illness that prevents further administration of treatment, - Patient requires more than 2 dose reductions (see Section 6.0)
At which point, the patient is taken off that particular treatment.
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duration of therapy on mpact

- Pre-defined mutation is not identified - Disease progression  
- All treatment regimens on study specific for the patient's mutation(s) of interest have been exhausted
- Intercurrent illness that prevents further administration of treatment, - Patient receives any other investigational agent or anticancer therapy - Patient decides to withdraw from the study.  
At which point, the patient is taken off the MPACT study.
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5.6 duration of follow-up

Patients in whom a pre-defined mutation is not identified will be taken off study, and no studyspecific follow up will be performed. Patients who receive study drug will be followed for 30 days after the last dose is administered or until one of the following occurs: patient enrolls on another protocol, patient receives standard of care, or death, whichever comes first. The followup will consist of a phone call between Days 27-30 after the last dose to evaluate adverse events that were ongoing and any new events that might be deemed related to the therapy. Unacceptable toxicities (i.e., AEs related to the intervention) that have not resolved by Day 30 post-treatment will be followed via biweekly phone calls until stabilization or resolution.
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5.7 criteria for removal from

Patients will be removed from the MPACT study for one of the following reasons:
- mutation of interest not detected on pre-treatment biopsy
- inability to obtain pre-treatment biopsy on study - completion of 30-day follow-up period
- toxicities are unresolved but stabilized
- patient enrolls on another protocol - patient receives standard of care
- pregnancy
- death The reason for study removal and the date the patient was removed must be documented in the medical record.
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6. dosing delays/dose modifications 6.1

Non-hematologic toxicities should have resolved to ≤ Grade 1 (except electrolyte abnormalities, which should resolve to ≤ Grade 2) and hematologic toxicities 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. The treatment day count will continue through days when doses are held. A new cycle will not start until the patient starts dosing on the next cycle. Treatment may be delayed for toxicity a maximum of 2 weeks beyond the actual cycle length; in case toxicities do not resolve as defined above, the patient will not receive further treatment with that regimen and will receive no further therapy on this protocol and will be followed for resolution of toxicities. Patients will be allowed up to 2 dose reductions before being taken off a treatment regimen.  
| Drug          | Dose and Schedule    | Dose Level -1        | Dose Level -2        |
|---------------|----------------------|----------------------|----------------------|
| Veliparib:    | 40 mg po BID d1-7    | 20 mg po BID d1-7    | 20 mg po BID d1-7    |
| Temozolomide: | 150 mg/m2 po qd d1-5 | 150 mg/m2 po qd d1-5 | 100 mg/m2 po qd d1-5 |  
For the purposes of dose reduction, the following dose levels will be used:  
| Drug             | Dose and Schedule      | Dose Level -1          | Dose Level -2          |
|------------------|------------------------|------------------------|------------------------|
| AZD1775:         | 225 mg po BID x5 doses | 175 mg po BID x5 doses | 175 mg po BID x5 doses |
| Carboplatin:     | AUC5 IV d1             | AUC 5 IV d1            | AUC 4 IV d1            |
| Everolimus:      | 10 mg po qd            | 5 mg po qd             | 2.5 mg po qd           |
| Trametinib DMSO: | 2 mg qd x28            | 1.5 mg qd x28          | 1 mg qd x28            |  
Dose modifications will only be made for adverse events that are felt to be related to study drug. Non-hematologic toxicities should have resolved to Grade ≤ 1 (except electrolyte abnormalities, which should resolve to Grade ≤ 2) and hematologic toxicities should have resolved to grade 2 or less prior to starting the next cycle. Doses will not be held or changed for alopecia, any grade lymphopenia, leucopenia in the absence of neutropenia, nausea/vomiting/diarrhea (unless it is refractory to palliative treatment), or electrolyte abnormalities. Patients receiving Veliparib who have persistent myelosuppression should be evaluated for the possible development of AML/MDS using a bone marrow aspirate with cytogenetics (Section 6.4).  
6.1.1 **Grade 2 Drug-Related Toxicity:** No changes will be made to the study treatment for Grade 2 toxicities.  
6.1.2 **Grade 3-4 Drug-Related Non-Hematologic Toxicities:** Doses will be held until toxicities recover to Grade ≤ 1 (with the exception of electrolyte abnormalities which should resolve to grade 2 or less; no dose adjustments will be made for electrolyte abnormalities) prior to re-initiating therapy at the next lower dose level.  
6.1.3 **Grade 3 Drug-Related Hematologic Toxicities:** Doses will be held until hematologic toxicities (except lymphopenia, leucopenia in the absence of neutropenia) have resolved to Grade ≤ 2 or baseline prior to re-starting study treatment. Therapy will be re-initiated at the same dose level.  
6.1.4 **Grade 4 Drug-Related Hematologic Toxicities:** Doses will be held until hematologic toxicities (except lymphopenia, leucopenia in the absence of neutropenia) have resolved to ≤ Grade 2 or baseline prior to re-starting study treatment. Therapy will be re-initiated at the next lower dose level.
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6.2 agent-specific dose modifications trametinib

Visual changes have been observed in patients receiving trametinib, and can be caused by retinal pigment epithelial detachments (RPED) or Retinal Vein Occlusion (RVO). Patients are required to have a standard ophthalmic exam performed by an ophthalmologist at baseline, at the start of cycle 2, and any time patients report visual disturbance. The exam will include best corrected visual acuity, visual field examination, tonometry, slit lamp biomicroscopic examination, and indirect fundoscopy. Optical coherence tomography may be performed at scheduled visits and if retinal abnormalities are suspected. Other types of ancillary testing including visual field examination, fundus photography, and fluorescein angiography may also be indicated as determined by clinical exam. Special attention should be given to retinal (e.g., RPED) or retinal vein abnormalities (e.g., RVO). Guidelines regarding event management and dose reduction for visual changes considered to be related to study treatment are provided in the table below.  
| Management and Trametinib Dose Modification for Visual Changes and/or Ophthalmic Examination Findings                                                                                                                                                                              |                                                                                                          |                                                                                                                                                                                                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Event                                                                                                                                                                                                                                                                              |                                                                                                          |                                                                                                                                                                                                                                                                                                      |
| CTCAE Grade                                                                                                                                                                                                                                                                        | Management Guideline                                                                                     | Dose Modification                                                                                                                                                                                                                                                                                    |
| Grade 1*                                                                                                                                                                                                                                                                           | •Consult ophthalmologist                                                                                 | - If dilated fundus examination cannot be performed within 7                                                                                                                                                                                                                                         |
| within 7 days of onset.                                                                                                                                                                                                                                                            | days of onset, hold trametinib until RPED and RVO can be  excluded by retina specialist/ophthalmologist. |                                                                                                                                                                                                                                                                                                      |
| - If RPED and RVO excluded, continue/or restart trametinib at  same dose level. - If RPED suspected/diagnosed: See RPED dose modification  table below (following this table); report as SAE. - If RVO diagnosed: Permanently discontinue trametinib  and report as SAE.           |                                                                                                          |                                                                                                                                                                                                                                                                                                      |
| Grade 2 and                                                                                                                                                                                                                                                                        | •Consult ophthalmologist                                                                                 | - Hold trametinib                                                                                                                                                                                                                                                                                    |
| Grade 3                                                                                                                                                                                                                                                                            | immediately.                                                                                             | - If RPED or RVO excluded, restart trametinib at same dose  level after visual AE is < grade 1. If no recovery within 3  weeks, discontinue trametinib - If RPED diagnosed: See RPED dose modification table  below; report as SAE. - If RVO: Permanently discontinue trametinib and report  as SAE. |
| Grade 4                                                                                                                                                                                                                                                                            | •Consult ophthalmologist  immediately. •Report as SAE.                                                   | - Hold Trametinib - If RPED/RVO excluded, may restart trametinib at same or  reduced dose after discussion with the CTEP Medical  Monitor. - If RVO or RPED, permanently discontinue trametinib.                                                                                                     |
| Abbreviations: RPED = retinal pigment epithelial detachments; RVO = retinal vein occlusion; SAE = serious  adverse event *If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but  ophthalmic examination is not required. |                                                                                                          |                                                                                                                                                                                                                                                                                                      |  
| Trametinib Dose Modification for RPED                                                                     |                                                                                                                                                                                                                                                                                     |
|-----------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Event                                                                                                     |                                                                                                                                                                                                                                                                                     |
| CTCAE Grade                                                                                               | Action and Dose Modification                                                                                                                                                                                                                                                        |
| Grade 1 RPED(Asymptomatic;  clinical or diagnostic observations  only)                                    | •Continue treatment with retinal evaluation monthly until resolution. If  RPED worsens, follow instructions below.                                                                                                                                                                  |
| Grade 2-3 RPED(Symptomatic  with mild to moderate decrease in  visual acuity; limiting instrumental  ADL) | - Interrupt trametinib. •Retinal evaluation monthly. - If improved to ≤ Grade 1, restart trametinib with one dose level reduction  (reduced by 0.5 mg) or discontinue in patients taking trametinib 1 mg  daily. - If no recovery within 4 weeks permanently discontinue trametinib |
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6.2.2 rash

Rash is a frequent AE observed in patients receiving trametinib DMSO (Investigator's Brochure, 2012). Recommendations for supportive care and guidelines for dose modifications for rash are based on experience with other MEK inhibitors and EGFR inhibitors [79, 80].  
| Guidelines for Supportive Care of Rash Type of Care Action Prevention/Prophylaxisa - Avoid unnecessary exposure to sunlight. - Apply broad-spectrum sunscreen (containing titanium dioxide or zinc oxide)  with a skin protection factor (SPF) ≥15 at least twice daily. - Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol  cream) on dry areas of the body at least twice daily. - Topical steroids and antibiotics should be applied at least twice daily, starting  on Day 1 of study treatment, to body areas such as face, chest, and upper back.  - Use mild-strength topical steroid (hydrocortisone 1% cream) or topical  antibiotic (e.g., clindamycin) or oral antibiotics (e.g., doxycycline 100 mg  BID, minocycline 100 mg BID). Symptomatic Careb - Pruritic lesions: Cool compresses and oral antihistamine therapies. - Fissuring lesions: Monsel's solution, silver nitrate, or zinc oxide cream. - Desquamation: Thick emollients and mild soap. - Paronychia: Antiseptic bath, local potent corticosteroids in addition to  antibiotics; if no improvement, consult dermatologist or surgeon. - Infected lesions: Appropriate bacterial/fungal culture-driven systemic or  topical antibiotics. a Rash prophylaxis is recommended for the first 6 weeks of study treatment. b Patients who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation  for symptomatic/supportive care management.   |
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| Trametinib DMSO Dose Modification Guidelines and Management for Rash Rash Severity Management Guideline Dose Modification Grade 1 - Initiate prophylactic and  symptomatic treatment measures.1 - Use moderate strength topical  steroid.2 - Reassess after 2 weeks. - Continue trametinib. - If rash does not recover to baseline within 2 weeks  despite best supportive care, reduce trametinib  DMSO by one dose level. 3 Grade 2 - Initiate prophylactic and  symptomatic treatment measures.1 - Use moderate strength topical  steroid.2 - Reassess after 2 weeks. - Reduce trametinib by one dose level. - If rash recovers to ≤ grade 1 within 2 weeks,  increase dose to previous dose level. - If no recovery to ≤ grade 1 within 2 weeks,  interrupt trametinib until recovery to ≤ grade 1. - Restart trametinib at reduced dose level.3 Grade ≥3 - Use moderate strength topical  steroids PLUS oral methylprednisolone dose pack.2 - Consult dermatologist. - Interrupt trametinib until rash recovers to ≤ grade 1. - Restart with trametinib reduced by one dose  level.3,4 - If no recovery to ≤ grade 2 within 4 weeks,  permanently discontinue trametinib. 1. Rash prophylaxis is recommended for the first 6 weeks of study treatment. 2. Moderate-strength topical steroids: Hydrocortisone 2.5% cream or fluticasone priopionate 0.5% cream. 3. Approval of CTEP Medical Monitor is required to restart study treatment after >4 weeks of interruption. 4. Trametinib may be escalated to previous dose level if no rash is evident 4 weeks after restarting study treatment.   |
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6.2.3 diarrhea

Episodes of diarrhea have occurred in patients receiving trametinib DMSO (Investigator's Brochure, 2012). Other frequent causes may include concomitant medications (e.g., stool softeners, laxatives, antacids, etc.), infections by *C. difficile* or other pathogens, or partial bowel obstruction. Those conditions should be excluded. Guidelines regarding management and dose modification for diarrhea considered related to trametinib are provided in the table below.  
| to trametinib are provided in the table below.   |
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| Management and Trametinib DMSO Dose Modification Guidelines for Diarrhea CTCAE Grade Adverse Event Management Action and Dose Modification Uncomplicated  Diarrhea,1 Grade 1 or 2 - Diet: Stop all lactose containing products; eat  small meals, BRAT-diet (banana, rice, apples,  toast) recommended. - Hydration: 8-10 large glasses of clear liquids  per day (e.g., Gatorade or broth). - Loperamide3 : Initially 4 mg, followed by 2 mg  every 4 hours or after every unformed stool;  maximum 16 mg/day. Continue until diarrheafree for 12 hours. - Diarrhea >24 hours: Loperamide 2 mg every 2  hours; maximum 16 mg/day. Consider adding  oral antibiotics. - Diarrhea >48 hours: Loperamide 2 mg every 2  hours; maximum 16 mg/day. Add budesonide or other second-line therapies (otreotide, or  tincture of opium) and oral antibiotics. - Continue trametinib DMSO. - If diarrhea is grade 2 for > 48 h, interrupt trametinib until diarrhea resolves to grade ≤1. - Restart trametinib at the same dose  level - If treatment delay is > 14 days,  discontinue trametinib. Uncomplicated  Diarrhea,1 Grade 3 or 4 - Clinical evaluation mandatory. - Loperamide3 : Initially 4 mg, followed by 2 mg  every 4 hours or after every unformed stool;  maximum 16 mg/day. Continue until diarrheafree for 12 hours. - Oral antibiotics and second-line therapies if  clinically indicated - Hydration: Intravenous fluids if clinically  indicated. - Antibiotics(oral or intravenous) if clinically  indicated. - Intervention should be continued until the  subject is diarrhea-free for ≥24 hours. - Intervention may require hospitalization for  subjects at risk of life-threatening  complications. - Interrupt trametinib until diarrhea  resolves to ≤ grade 1. - Restart with trametinib reduced by one  dose level.4 - If 3 dose reductions of study treatment  are clinically indicated, permanently  discontinue trametinib DMSO. - If treatment delay is >21 days,  discontinue trametinib. Any Complicated  Diarrhea2 1. Uncomplicated diarrhea defined by the absence of symptoms such as cramping, nausea/vomiting, ≥ grade 2,  decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring  intravenous fluid substitution. 2. Complicated diarrhea defined by the presence of symptoms such as cramping, nausea/vomiting, ≥ grade 2,  decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring  intravenous fluid substitution. 3. Loperamide should be made available prior to start of study treatment so loperamide administration can begin at  the first signs of diarrhea. 4. Escalation of trametinib to previous dose level is allowed after consultation with the medical monitor and in the  absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction.41                                                  |
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6.2.4 liver chemistry changes

| Trametinib Dose Modification for Liver Function Test Abnormalities Event Treatment modifications and assessment/monitoring ALT ≥3x ULN but <5x ULN  and TB <2x ULN, without  symptoms considered related  to liver injury or  hypersensitivity and who can  be monitored weekly for 4  weeks May continue study drug. Report as SAE if CTEP-AERS reporting criteria are met. If liver chemistry stopping criteria are met any time, proceed as  described below. MONITORING: Repeat LFT (ALT, AST, ALK, bilirubin) until they return to  normal/baseline or stabilise (LFT may be every 2 weeks after 4 weeks  if ALT <3x ULN and TB <2 ULN). Criteria for discontinuing study drug: When any of the liver  stopping criteria below is met,  discontinue trametinib Immediately discontinue study treatment. Do not restart/rechallenge unless approved by CTEP trametinib medical  monitor.  Report as SAE if: 1) CTEP-AERS reporting criteria are met, or 2)  patients meet criteria 1-2. Perform liver event ASSESSMENT AND WORKUP (see below). Monitor the subject until liver chemistriesresolve, stabilize, or return to  baseline (see MONITORING below). If applicable, provide details on required follow up assessments (e.g.,  follow up for overall survival or disease recurrence or progression).  ALT ≥3xULN and bilirubin  ≥2x ULN or >35% direct  bilirubin 1, 2 ALT  3xULN and INR >1.5,  if INR measured2 (INR  threshold does not apply if  subject is on anticoagulant) ALT ≥5x ULN ALT ≥3x ULN persists for 4  weeks ALT ≥3x ULN and cannot be  monitored weekly for 4 weeks ALT ≥3x ULN associated with  symptoms3 (new or worsening)  believed to be related to liver  injury or hypersensitivity MONITORING: In patients stopping for criteria 1-2 (with abnormal TB and INR,  indicating potentially more significant liver toxicities): Repeat liver chemistries(ALT, AST, ALK, bilirubin) and perform liver  event follow-up assessments within 24 hours. Monitor subjects twice weekly until LFT return to normal/baseline or  stabilize. A specialist or hepatology consultation is recommended. In patients stopping for criteria 2-6: Repeat LFTand perform liver event follow up assessments within  24-72 hrs  Monitor subjects weekly until LFTs return to normal/baseline or  stabilize. ASSESSMENT and WORKUP: Viral hepatitis serology.4 If possible, obtain blood sample for PK analysis.5 Serum CPK and LDH. Fractionate bilirubin, if total bilirubin ≥2x ULN. CBC with differential to assess eosinophilia. Record clinical symptoms of liver injury, or hypersensitivity on AE  CRF. Record concomitant medications (including acetaminophen, herbal  remedies, other over the counter medications). Record alcohol use.   |
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| Trametinib Dose Modification for Liver Function Test Abnormalities Event Treatment modifications and assessment/monitoring Additional work up for patient stopping for criteria 1-2 (with abnormal  TB and INR, indicating potentially more significant liver toxicities): Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver  kidney microsomal antibodies, and quantitative total immunoglobulin G  (IgG or gamma globulins). Serum acetaminophen adduct HPLC assay (in subjects with likely  acetaminophen use in the preceding). If there is underlying chronic hepatitis B (e.g. positive hepatitis B  surface antigen): quantitative hepatitis B DNA and hepatitis delta  antibody.6 Liver imaging (ultrasound, MRI, CT) and /or liver biopsy. Footnotes: 1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin  fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, which  indicates direct bilirubin elevations and suggesting liver injury. 2. All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT 3x ULN and  INR >1.5 (if INR measured) may indicate severe liver injury (possible "Hy's Law"). INR measurement  is not required, and the threshold value stated will not apply to subjects receiving anticoagulants. 3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting,  right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such  as fever, rash, or eosinophilia) 4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody  (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM  antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody  5. PK sample is desired if feasible. Record the date/time of the PK blood sample draw and the  date/time of the last dose of study treatment prior to blood sample draw on the CRF. If the date or time  of the last dose is unclear, provide the subject's best approximation. If the date/time of the last dose  cannot be approximated OR a PK sample cannot be collected in the time period indicated above, do not  obtain a PK sample.  6. If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D  RNA virus (where needed) (Le Gal et al., 2005).   |
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6.2.5 pneumonitis

Pneumonitis has been observed in patients receiving trametinib DMSO. To reduce the risk of pneumonitis, patients will be monitored closely for symptoms and evaluated with imaging and functional tests. Dose modification and supportive care guidelines for pneumonitis are described in the tables below.  
| Pneumonitis Guidelines for Trametinib Monotherapy CTCAE  Grade Adverse Event Management   | Action and Dose Modification                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                    |
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| Grade 1                                                                                   | CT scan (high-resolution with lung windows)  recommended. Work-up for infection. Monitoring of oxygenation via pulseoximetry recommended. Consultation with pulmonologist  recommended. Continue trametinib at current dose.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                    |
| Grade 2                                                                                   | CT scan (high-resolution with lung  windows). Work-up for infection. Consult pulmonologist. Pulmonary function tests: If < normal, repeat  every 8 weeks until ≥ normal. Bronchoscopy with biopsy and/or BAL  recommended. Symptomatic therapy including  corticosteroids if clinically indicated. Interrupt trametinib until recovery to  grade ≤1. Restart treatment with trametinib  reduced by one dose level Escalation to previous dose level  after 4 weeks may be considered  after consultation with medical  monitor  If no recovery to grade ≤1 within 4  weeks, permanently discontinue  trametinib |                                                                                                                                                                                                                                    |
| Grade 3                                                                                   | Same as grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Interrupt trametinib until recovery to  grade ≤1. After consultation with medical  monitor, trametinib may be restarted  reduced by one dose level If no recovery to grade ≤1 within 4  weeks, permanently discontinue  trametinib |
| Grade 4                                                                                   | Same as grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Permanently discontinue trametinib.                                                                                                                                                                                                |
| Abbreviations: BAL = bronchoalveolar lavage; CT = computed tomography.                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                    |
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6.2.6 reduced left ventricular ejection

Decreases of LVEF have been observed in patients receiving trametinib DMSO. Therefore, ECHOs must be performed in regular intervals outlined in the Study Calendar. The same procedure (either ECHO or MUGA, although ECHO is preferred) should be performed at baseline, every three cycles, and as clinically indicated.  
| Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease Clinic LVEF-drop (%) or Action and Dose CTCAE grade Modification Asymptomatic Absolute decrease of >10% in  LVEF compared to baseline  and ejection fraction below the  institution's LLN. - Interrupt trametinib and repeat ECHO/MUGAwithin 2  weeks.a - If the LVEF recovers within 4 weeks (defined as LVEF  ≥LLN and absolute decrease ≤10% compared to baseline): − Consult with the CTEP trametinib medical monitor and  request approval for restart. − Restart treatment with trametinib at reduced dose by one  dose level. − Repeat ECHO/MUGA2, 4, and 12 weeks after re-start;  continue in intervals of 12 weeks thereafter. - If LVEF does notrecover within 4 weeks: − Consult with cardiologist. − Permanently discontinue trametinib. − Repeat ECHO/MUGAafter 2, 4, 8, 12, and 16 weeks or  until resolution. − Consult with the CTEP trametinib medical monitor.c Symptomaticb - Grade 3: resting LVEF 39- 20% or >20% absolute  reduction from baseline - Grade 4: Resting LVEF  ≤20%. - Permanently discontinue trametinib. - Report as SAE. - Consult with cardiologist. - Repeat ECHO after 2, 4, 8, 12, and 16 weeks or until  resolution. a If ECHO/MUGAdoes not show LVEF recovery after 2 weeks, repeat ECHO/MUGA2 weeks later. b Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after  restarting of trametinib. Approval from the CTEP trametinib medical monitor is required. c Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema   |
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| Trametinib Withholding and Stopping Criteria for QTc Prolongation                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                              |
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| QTc Prolongationa                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Action and Dose Modification |
| - QTcB ≥501 msec, or - Uncorrected QT >600 msec, or - QTcB >530 msec for subjects with  bundle branch block - Interrupt study treatment until QTcB prolongation resolves to grade 1 or  baseline. - Test serum potassium, calcium, phosphorus, and magnesium. If  abnormal, correct per routine clinical practice to within normal limits. •Review concomitant medication usage for a prolonged QTc. •Restart at current dose level.b - If the event does not resolve or recurs after restarting, permanently  discontinue study treatment. Abbreviations: msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using Bazett's formula a Based on average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval,  obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to  determine if study treatments should be interrupted or discontinued. b if the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the investigator  and the CTEP trametinib medical monitor agree that the subject will benefit from further treatment. |                              |
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6.2.7 qtc prolongation 6.2.8 hypertension

Increases in blood pressure (BP) have been observed in patients receiving trametinib DMSO. Recommendations for BP monitoring and management are provided below. Monitoring: All BP assessments should be performed under the following optimal conditions:
- The subject has been seated with back support, ensuring that legs are uncrossed and flat on the floor.  
- The subject is relaxed comfortably for at least 5 minutes. - Restrictive clothing has been removed from the cuff area, and the right cuff has been selected.  
- The subject's arm is supported so that the middle of the cuff is at heart level.  
- The subject remains quiet during the measurement.  
- In subjects with an initial BP reading within the hypertensive range, a second reading should be taken at least 1 minute later, with the two readings averaged to obtain a final BP measurement. The averaged value should be recorded in the eCRF.  
- Persistent hypertension is defined as an increase of systolic blood pressure (SBP)
>140 mmHg and/or diastolic blood pressure (DBP) >90 mmHg in three consecutive visits with blood pressure assessments from two readings as described above. Visits to monitor increased blood pressure can be scheduled independently from the perprotocol visits outlined in the study calendar. Ideally, subsequent blood pressure assessments should be performed within 1 week.  
| Event                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Management Guideline   | Dose Modification   |
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| Definitions used in the table: − Persistent hypertension: Hypertension detected in two separate readings during up to three subsequent visits. − Well-controlled hypertension: Blood pressure of SBP ≤140 mmHg and DBP ≤90 mmHg in two separate  readings during up to three subsequent visits. − Symptomatic hypertension: Hypertension associated with symptoms (e.g., headache, light-headedness,  vertigo, tinnitus, episodes of fainting or other symptoms indicative of hypertension) that resolve after the blood  pressure is controlled within the normal range. − Asymptomatic hypertension: SBP >140 mmHg and/or DBP >90 mmHg in the absence of the above symptoms. (Scenario A) - Asymptomatic and persistent SBP  of ≥140 and <160mmHg, or DBP  ≥90 and <100 mmHg,  or Clinically significant increase in  DBP of 20 mmHg (but still below  100 mmHg). Continue trametinib at the current  dose. - Adjust current or initiate new  antihypertensive medication(s). - Titrate antihypertensive  medication(s) during the next 2  weeks to achieve well-controlled  BP. If BP is not well-controlled  within 2 weeks, consider referral to  a specialist and go to scenario (B). (Scenario B) - Asymptomatic SBP ≥160 mmHg,  or DBP ≥100 mmHg,  or Failure to achieve well-controlled BP  within 2 weeks in Scenario A. - Adjust current or initiate new  antihypertensive medication(s). - Titrate antihypertensive  medication(s) during the next 2  weeks to achieve well-controlled  BP. - Interrupt trametinib if clinically  indicated. - Once BP is well-controlled, restart  trametinib reduced by one dose  level. a (Scenario C) - Symptomatic hypertension  or Persistent SBP ≥160 mmHg, or DBP  ≥100 mmHg, despite  antihypertensive medication and  dose reduction of trametinib - Adjust current or initiate new  antihypertensive medication(s). - Titrate antihypertensive  medication(s) during the next 2  weeks to achieve well-controlled  BP. •Referral to a specialist for further  evaluation and follow-up is  recommended. - Interrupt trametinib. - Once BP is well-controlled, restart  trametinib reduced by one dose  level. a (Scenario D) Refractory hypertension  unresponsive to above interventions  or hypertensive crisis. Continue follow-up per protocol. Permanently discontinue  trametinib. a. Escalation of trametinib to previous dose level can be considered if BPs remain well controlled for 4 weeks  after restarting of trametinib. Approval from Medical Monitor is required. |                        |                     |  
Management and Trametinib Dose Modification for Hypertension
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6.3 agent-specific dose modifications everolimus

6.3.1 **Hyperglycemia:** Grade 2 or higher elevations in blood glucose with the patient non-fasting should be confirmed by obtaining fasting values prior to making any treatment decisions. Grade 3 will result in temporary dose reduction, management with appropriate therapy, and re-initiation at a lower dose.  
6.3.2 **Hyperlipidemia and Hypertriglyceridemia:** Grade 3 (measured by cholesterol and triglycerides) will result in holding study drug until resolution of toxicity to Grade 2 or less, at which point study drug administration will be reinstituted at the next lowest dose level. Grade 4 elevation in either serum cholesterol or triglyceride levels will result in study drug discontinuation.  
6.3.3 **Skin Toxicity:** For patients with grade 1 toxicity, no specific supportive care is usually needed or indicated. Rash must be reported as an AE. Patients with grade 2 or higher toxicity may be treated with the following suggested supportive measures at the discretion of the investigator: oral minocycline, topical tetracycline, topical clindamycin, topical silver sulfadiazine, diphenhydramine, oral prednisolone (short course), topical corticosteroids, or pimecrolimus.  
6.3.4 Angioedema with concomitant use of angiotensin-converting enzyme (ACE)
inhibitors: 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).