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5.3.11 genetic counseling

If the research findings are verified in the CLIA certified lab, the subject will be offered the opportunity to come to NIH (at our expense) to have genetic education and counseling with the NCI Genetics Branch to explain this result. If the subject does not want to come to NIH, a referral to a local genetic healthcare provider will be provided (at their expense). This is the only time during the course of the study that incidental findings will be returned. No interrogations regarding clinically actionable findings will be made after the primary analysis.
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5.4 sample storage tracking and

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without appropriate approvals and/or agreements, if required.  
5.4.1 Samples Managed by Dr. Figg's Blood Processing Core (BPC) BPC contact information Please e-mail at NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 5.4.1.1 Sample Data Collection All samples sent to the Blood Processing Core (BPC) (Dr. Figg's lab) will be barcoded, with data entered and stored in the Labmatrix utilized by the BPC. This is a secure program, with access to limited to defined Figg lab personnel, who are issued individual user accounts. Installation of Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced back to participants without Labmatrix access. The data recorded for each sample includes the participant ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and freezer location. Participant demographics associated with the clinical center participant number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.). Sample barcodes are linked to participant demographics and limited clinical information. This information will only be provided to investigators listed on this protocol, via registered use of the Labmatrix. It is critical that the sample remains linked to participant information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate genotype with these variables.
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5.4.1.2 sample storage

Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -800C according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the NIH Intramural IRB approved protocol) and that any unused samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with NIH Intramural IRB approval. Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following NIH Intramural IRB approval of an additional protocol, granting the rights to use the material.  
If, at any time, a participant withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the participant, if so requested). The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be made per the requirements of section 7.2.  
5.4.2 Procedures for storage of participant samples in the Laboratory of Jane Trepel Contact the Trepel Lab by email (Jane Trepel: trepelj@mail.nih.gov; Min-Jung Lee: leemin@mail.nih.gov; Akira Yuno: akira.yuno@nih.gov and Sunmin Lee: leesun@mail.nih.gov) when the participant is scheduled and by phone as soon as the blood is drawn at 240-760-6330. A lab member will come to pick up the blood. Please keep blood at ambient temperature. Members of the lab will enter the samples into a secure password protected participant's sample tracking database (Translational Pharmacodynamics Research Group Patient Sample Management System) and process the samples. Sample barcodes are linked to participant demographics and limited clinical information. This information will only be provided to investigators listed on this protocol. It is critical that the sample remains coded and linked to participant information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate with these variables. Blood samples will be stored initially in the Trepel Lab in the Magnuson Clinical Center. If, at any time, a subject withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the participant, if so requested). When a participant withdraws consent the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved. The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be made per the requirements of section 7.2.  
5.4.3 Procedures for storage of participant samples in the Laboratory of Dr. Redon Participant samples, collected for the purpose of research under NIH Intramural IRB approved protocols, may be archived in the Dr. Redon laboratory. All data associated with archived clinical research samples is entered into the web-based NCI Labmatrix database, centralized system with access controlled via centralized login. Access to this database is limited to Dr Redon research staff, requiring individual login and password. All staff in the Dr Redon laboratory have received annually updated NIH/CIT training and maintain standards of computer security. The data recorded for each sample may include the participant ID, trial name/protocol number, date drawn/collected, treatment cycle/post-transplant time point, cell source (e.g. peripheral blood, marrow, tissue) as well as box and freezer location. All received samples will receive a unique bar code number, which will be added to the sample NCI Labmatrix database. Only this bar code will be recorded on the sample vial and the vials will not be traceable back to participants without authorized access to the NCI Labmatrix database.  
Samples are stored in freezers at -800C (sera, plasma, tissue samples) or under liquid nitrogen
(cells), according to stability requirements. These freezers are located onsite at the Dr. Redon laboratory. Access to samples from a protocol for research purposes will be by permission of the Principal Investigator At least 24 hours prior to the start of the study, the research nurse will contact Dr. Redon in Dr. Aladjem's lab (DTB-LMP/CCR/NCI, Bldg. 37/ Rm 5056) to inform him when samples will be taken (Tel: 240-760-7338 (L); 301-760-6275 (Cell); redonc@mail.nih.gov). Dr. Redon will provide tubes for collecting the plucked hairs. The tubes contain ice cold PBS labeled with the date/time of sampling, the protocol, and the unique identifier. Dr. Redon should be notified of when the samples should be picked up.
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5.4.4 procedures for storage of

Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) where they are examined grossly and relevant portions are fixed, embedded in paraffin and sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not embedded in paraffin is stored in formalin for up to three months, in accordance with College of American Pathologists/Joint Commission on Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, the slides and tissue blocks are stored indefinitely in the LP's clinical archives. All specimens are catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed when the appropriate IRB approval has been obtained. In some cases, this approval has been obtained via the original protocol on which the participant was enrolled. 5.4.5 Procedures for storage of tissue and blood samples in the Laboratory of Dr. Kumar
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5.4.5.1 blood samples

The samples must be stored under conditions in which the analytes are known to be in stable conditions. The blood samples should be refrigerated during the short period, immediately after the centrifugation for plasma and serum, will be barcoded and stored in -80° freezer (Thermofisher TSX series) located in building 37, room 5056. Sample barcodes are linked to participant demographics and limited clinical information. The -80° freezer should be locked all the time, and the key should be in the safe custody of the lab manager. The samples should be entered in the LabMatrix software. PI and research personal can access LabMatrix and locate the samples at any time for future use. The samples should be logged in the research laboratory. Concerned research personnel can access the samples, and the samples should be returned to the same location if leftover research materials is available. The samples should be maintained under appropriate conditions until disposal is authorized. Disposal of the sample should also be recorded in the LabMatrix in the system.
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5.4.5.2 tissue samples

The biopsy sample will be collected in a liquid nitrogen canister and transferred to the research laboratory. The barcoded samples should be stored in -80° freezer and entered in the Labmatrix software. The -80° Freezer should be locked all the time, and the key should be in the safe custody of the lab manager. The samples should be entered in the LabMatrix software. Sample barcodes are linked to participant demographics and limited clinical information. PI and research personnel can access LabMatrix and locate the samples at any time for future use. The samples should be
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5.4.5.2 tissue samples

logged in the research laboratory. Concerned research personal can access the samples, and the samples should be returned to the same location if leftover research materials is available. The samples should be maintained under appropriate conditions until disposal is authorized. Disposal of the sample should also be recorded in the LabMatrix in the system. Samples will be disposed of after the final report is issued or when required by directives given in the informed consent paperwork for clinical studies. The research laboratory should document that the samples have been disposed of (LabMatrix) at the time of disposal. For the sample disposal, we will follow the NIH regulations. 5.4.6 Procedures for Storage of PLX038 Coagulation Assay Blood Samples in the Department of Laboratory Medicine (DLM)
The DLM provides laboratory testing for all Clinical Center inpatients and clinic outpatients. The hospital-wide information system (CRIS) is used for ordering a request analyte. The laboratory information system (LIS) is used for reporting laboratory tests and is interfaced with CRIS. Test results are available in CRIS as soon as they are verified in the LIS.  
Tests that are run by DLM will be performed on a fresh sample or on batched frozen samples. During this time, the plasma will be separated and stored at -80° C in a DLM freezer. Frozen samples will be batched and sent to Mayo Clinic periodically. DLM uses patient labels generated from LIS system with patient identification such as MRN, LIS \# and patient full name on each aliquot sample when stored at -80° C. 5.4.7 Protocol Completion/Sample Destruction All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are remaining at the completion of the protocol will be stored in the conditions described in sections above. The study will remain open so long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or if a subject withdraws consent for their continued use, at which time they will be destroyed. If the participant withdraws consent the participant's data will be excluded from future distributions, but data that have already been distributed for approved research use will not be able to be retrieved. The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be made per the requirements of section 7.2.
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data collection and evaluation 6.1

The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data capture system provided by the NCI CCR and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. All adverse events, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Document AEs from the first study intervention, Study Day 1 of Cycle 1 through 30 days after study agent (s) administration. Beyond 30 days after the last study treatment administration, only adverse events which are serious and related to the study intervention need to be recorded.  
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory abnormality is characterized by any of the following:  
- Results in discontinuation from the study
- Is associated with clinical signs or symptoms - Requires treatment or any other therapeutic intervention - Is associated with death or another serious adverse event, including hospitalization.  
- Is judged by the Investigator to be of significant clinical impact
If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the participant's outcome.  
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect subject confidentiality and trial data has occurred, this will be reported expeditiously per requirements in section **7.2.1**.
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6.2 data sharing plans 6.2.1

At the time of publication or shortly thereafter, the PI will share coded linked human data generated in this research for future research
− in a NIH-funded or approved public repository: clinicaltrials.gov and dbGaP  
− in BTRIS
− in publication and/or public presentations  
− with approved outside collaborators under appropriate agreements 6.2.2 Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy.
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6.3 response criteria

For the purposes of this study, participants should be re-evaluated for response every 9 weeks (+/- 1 week). Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [55, 56]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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6.3.1 disease parameters

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as:
- By chest x-ray: >20 mm;  
- By CT scan:
o Scan slice thickness 5 mm or under as >10 mm with CT scan o Scan slice thickness >5 mm: double the slice thickness
- With calipers on clinical exam: >10 mm.
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same participant, these are preferred for selection as target lesions. Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 6.3.2 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used, and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound during the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain).  
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. 6.3.3 Response Criteria 6.3.3.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. 6.3.3.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a participant to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or *unequivocal progression* of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). 6.3.3.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| For Participants with Measurable Disease (i.e., Target Disease)   |                                                                   |                      |                       |                             |
|-------------------------------------------------------------------|-------------------------------------------------------------------|----------------------|-----------------------|-----------------------------|
| Target                                                            | Non-Target                                                        | New                  | Overall               | Best Overall Response       |
| Lesions                                                           | Lesions                                                           | when Confirmation is |                       |                             |
| Lesions                                                           | Response                                                          | Required*            |                       |                             |
| CR                                                                | CR                                                                | No                   | CR                    | >4 wks. Confirmation**      |
| CR                                                                | Non-CR/Non-PD                                                     | No                   | PR                    |                             |
| CR                                                                | Not evaluated                                                     | No                   | PR                    | ≥ 4 wks. Confirmation**     |
| PR                                                                | Non-CR/Non-                                                       | No                   | PR                    |                             |
| PD/not evaluated                                                  |                                                                   |                      |                       |                             |
| SD                                                                | Non-CR/Non-                                                       | No                   | SD                    | Documented at least once >4 |
| PD/not evaluated                                                  | wks. from baseline**                                              |                      |                       |                             |
| PD                                                                | PD                                                                |                      |                       |                             |
| Any                                                               | Yes or No                                                         | PD                   | no prior SD, PR or CR |                             |
| Any                                                               | PD***                                                             | Yes or No            | PD                    |                             |
| Any                                                               | Any                                                               | Yes                  |                       |                             |
| See RECIST 1.1 manuscript for further details.                    |                                                                   |                      |                       |                             |
| **                                                                | Only for non-randomized trials with response as primary endpoint. |                      |                       |                             |  
**
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.  
Note:
Participants with a global deterioration of health status requiring discontinuation of  
treatment without objective evidence of disease progression at that time should be
reported as "symptomatic deterioration." Every effort should be made to document the objective progression even after discontinuation of treatment.  
| Non-Target Lesions   | New Lesions   | Overall Response   |
|----------------------|---------------|--------------------|
| CR                   | No            | CR                 |
| Non-CR/non-PD        | No            | Non-CR/non-PD*     |
| Not all evaluated    | No            | nt evaluated       |  
| Version Date: 02/02/2023                                                                     |             |                  |
|----------------------------------------------------------------------------------------------|-------------|------------------|
| Non-Target Lesions                                                                           | New Lesions | Overall Response |
| PD                                                                                           |             |                  |
| Unequivocal PD                                                                               | Yes or No   |                  |
| Any                                                                                          | Yes         | PD               |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is      |             |                  |
| increasingly used as an endpoint for assessment of efficacy in some trials so to assign this |             |                  |  
category when no lesions can be measured is not advised
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6.3.3.4 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).  
The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.  
Duration of stable disease; Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
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toxicity criteria 6.4

The following adverse event management guidelines are intended to ensure the safety of each participant while on the study. The descriptions and grading scales found in the revised NCI
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site
( http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_50 ).
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nih reporting requirements / data

Please refer to definitions provided in Policy 801: Reporting Research Events found at:
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835\#Policies&Guidance800Series-ComplianceandResearchEventReportingRequirements.
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7.2 ohsrp office of compliance

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy Subjects Non-Compliance Human Research 802 found at:
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835\#Policies&Guidance800Series-ComplianceandResearchEventReportingRequirements .  
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies.  
7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found at:
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835\#Policies&Guidance800Series-ComplianceandResearchEventReportingRequirements.
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7.3 nci clinical director reporting

Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to the NCI Clinical Director/designee; therefore, a separate submission for these reports is not necessary. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 nih required data and

The clinical research team will meet on a weekly basis when participants are being actively treated on the trial to discuss each participant. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior participants. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each participant to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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7.4.2 safety monitoring committee (smc)

This protocol will be periodically reviewed by an intramural Safety Monitoring Committee.  
comprising physicians, biostatisticians and a lay member selected based on experience, area of expertise, reputation for objectivity, absence of conflicts of interest and knowledge of or experience with clinical trial research. Each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC based on the risks presented in the study. Protocols will not be reviewed if there is no accrual within the review period. The SMC will operate under the rules of an approved charter that will be written and reviewed at the organization meeting of the SMC. Each review will focus on unexpected protocol-specific safety issues that are identified during the conduct of the clinical trial. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
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sponsor protocol/safety reporting 8.1 definitions

Any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2)).
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8.1.2 serious adverse event (sae)

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
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- death

- A life-threatening adverse event (see section **8.1.3**)
- Inpatient hospitalization or prolongation of existing hospitalization o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for participant convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria
- Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly/birth defect. - Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the participant or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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8.1.3 life-threatening

An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the participant or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32).
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8.1.4 severity

The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 8.1.5 Relationship to Study Product All AEs will have their relationship to study product assessed using the terms: related or not related.  
- Related - There is a reasonable possibility that the study product caused the adverse event.  
Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
- Not Related - There is not a reasonable possibility that the administration of the study product caused the event.  
8.1.6 Adverse Events of Special Interest (AESI)
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8.1.6.1 rucaparib

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered adverse events of special interest (AESIs), as these events have been observed in participants exposed to cytotoxic chemotherapy (e.g., platinum and anthracyclines) used for treatment of ovarian cancer as well as with PARP inhibitors, including rucaparib. Per the Rucaparib Development Safety Update Report 9 issued on 08/11/2020 and IB version 08/23/2020, pneumonitis has been designated as an AESI. Investigators should implement immediately the reporting of any AE of pneumonitis, or any of the following AEs, irrespective of causality assessment and severity, as an AESI (both serious and non-serious) within 24 hours:  
- Pneumonitis
- Interstitial lung disease - Pulmonary fibrosis
- Acute interstitial pneumonitis
- Alveolitis necrotizing
- Alveolitis
- Hypersensitivity pneumonitis - Organizing pneumonia
The following AESIs are being added per Rucaparib DSUR version 11, dated 8/12/2022:  
- Teratogenicity - New primary malignancies - QTc interval prolongation
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8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution. SAEs will be:  
- Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
- Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
- Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor with the exception of any listed in section 8.4.
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8.3 reporting of serious adverse

Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited reporting requirements are found in section **8.4.**
All SAE reporting must include the elements described in section 8.2.  
SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
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8.4 waiver of expedited reporting

As death/hospitalization due to disease progression is part of the study objectives (CBR, OS and PFS) during Phase II and captured as endpoints in this study, death/hospitalization due to disease progression will not be reported in expedited manner to the sponsor during Phase II. However, if there is evidence suggesting a causal relationship between the study drug and the event, report the event in an expedited manner according to section 8.3.  
The Sponsor might request case summaries for those events if, upon review, the Sponsor determines that an aggregate safety report is required (21CFR312.32(c)(1)(iv)).
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8.6 reporting pregnancy

All required pregnancy reports/follow-up to OSRO will be submitted to: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. Forms and instructions can be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
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8.6.1 maternal exposure

If a participant becomes pregnant during the course of the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy become known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section **8.1.2**) should be reported as SAEs.  
The outcome of all pregnancies should be followed up and documented. 8.6.2 Paternal exposure Male participants should refrain from fathering a child or donating sperm during the study and for 6 months after the last dose of study drug(s). Pregnancy of the participant's partner is not considered to be an AE. The outcome of all pregnancies occurring from the date of the first dose until 6 months after the last dose should, if possible, be followed up and documented. Pregnant partners may be offered the opportunity to participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to provide data about the outcome of the pregnancy for safety reporting purposes.
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8.7 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
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8.8 sponsor protocol deviation reporting

A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or protocol-specific procedural requirements on the part of the participant, the Investigator, or the study site staff inclusive of site personnel performing procedures or providing services in support of the clinical trial. It is the responsibility of the study Staff to document any protocol deviation identified by the Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. The entries into the PDTS online application should be timely, complete, and maintained per CCR PDTS user requirements. In addition, any deviation to the protocol should be documented in the participant's source records and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations.
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clinical monitoring

Clinical site monitoring is conducted to ensure:  
- that the rights of the participants are protected; - that the study is implemented per the approved protocol, Good Clinical Practice and standard operating procedures; and,
- the quality and integrity of study data and data collection methods are maintained.
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory requirements. Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human subject protections and integrity of the study data. OSRO will determine the intensity and frequency of monitoring based on several factors, including study type, phase, risk, complexity, expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger CMP updates. OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit (SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) (IMVs), and a study Close-Out Visit (COV). Some monitoring activities may be performed remotely, while others will occur at the study site(s). Monitoring visit reports will describe visit activities, observations, and associated action items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating center (if applicable), and the Sponsor regulatory file. The site Monitor will inform the study team of any deviations observed during monitoring visits. If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per institutional and IRB guidance.
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statistical considerations 10.1 study objective

10.1.1 Primary Objectives  
- Phase I: To identify the maximum tolerated dose (MTD) of PLX038 in combination with rucaparib.  
- Phase II: To assess the efficacy with respect to clinical benefit rate (CBR) (CR+PR+SD) for 4 months according to Response Evaluation Criteria (RECIST 1.1) of a combination of PLX038
and rucaparib in previously treated participants with small cell lung cancer and extrapulmonary small cell carcinomas.  
10.1.2 Secondary Objectives
- To assess safety and tolerability of combined treatment of PLX038 and rucaparib  
- To determine the progression-free survival
- To determine overall survival
- To assess the clinical response rate (CRR) (CR+PR) according to Response Evaluation Criteria
(RECIST 1.1).
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10.2 sample size determination

The initial portion of the trial will be a phase I dose escalation study using a standard 3 + 3 design to determine the MTD over increasing dose levels of rucaparib. Prior to amendment version 03/19/2021, 8 patients were treated in phase I using the former dose escalation scheme. Beginning with amendment version 03/19/2021, with up to 3 new dose levels to be explored, no more than 8+18=26 evaluable participants will be treated in phase I. The phase II portion of the trial will be conducted using a Simon two-stage Minimax design to rule out an unacceptably low 10% clinical benefit rate (CBR: CR+PR+SD for 4 months) (p0=0.10) in favor of a targeted CBR of 30% (p1=0.30). Based on historical controls, observing a CBR of 20% would be considered clinically meaningful in this setting [24]. With alpha=0.10 and beta=0.10, the study will initially enroll 16 evaluable subjects. If 0-1 subjects have clinical benefit, then no more subjects will be enrolled in this cohort. If 2 or more of the first 16 subjects have clinical benefit, then accrual would continue to a total of 25 subjects. If there were 2-4 subjects with clinical benefit in 25 subjects, this would not be considered promising in this population. If there were 5 or more subjects of the 25 (20.0%) who have clinical benefit, this would be sufficiently interesting to warrant further study of this combination in a future randomized trial comparing this combination with the standard of care. The probability of early termination is 51.5% if the true response rate were 10%. In addition, up to 10 participants with extrapulmonary small cell cancers may be enrolled on the protocol. The CBR of these participants will not be included in the primary statistical analysis and will be described in an exploratory manner. The theoretical maximum number of subjects required to determine the MTD in the phase I portion of the study is 26 subjects (8 from before amendment version 03/19/2021 and 6 per dose level for 3 dose levels, although as few as 8+12=20 subjects in 3 dose levels could ascertain the MTD including the participants previously treated before amendment version 03/19/2021). For the phase II portion of the study, 25 evaluable subjects with SCLC and 10 subjects with extrapulmonary small cell cancers are to be recruited. Depending on the number of subjects needed to determine the MTD, and if any of the participants enrolled on the MTD level during phase I have SCLC are eligible for inclusion among those on the phase II portion, planned enrollment is expected to be no more than 26+25+10=61 participants. To allow for the possibility of a small number of inevaluable participants, the accrual ceiling will be set at 65. If the study can accrue 12-15 participants per year, accrual is expected to be completed in 4-5 years.
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10.3 populations for analyses

All participants who received at least one dose of both treatments and had at least one post-baseline tumor assessment will be evaluated for response. In addition, any treated participants who exhibited clinical progression before being evaluated for clinical response will be included in the analysis. Participant will be eligible for the DLT evaluation if at least ≥85 percent of rucaparib scheduled doses were taken within the DLT period.
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10.4 statistical analyses 10.4.1 general

The fraction of participants who experience a clinical benefit (CR+PR+SD longer than 4 months) will be reported along with confidence intervals. 10.4.2 Analysis of the Primary Efficacy Endpoints The fraction of evaluable participants who experience clinical benefit will be determined along with a two-sided 95% confidence interval. 10.4.3 Analysis of the Secondary Efficacy Endpoints The safety of the treatment will be monitored, and any toxicities identified will be reported by type and grade. Among participants in the phase IIA cohort, overall survival (OS) and progression free survival (PFS) will be calculated from the on-study date using the Kaplan-Meier method, along with 95% confidence intervals on the median OS and PFS. The fraction of participants who experience a clinical response (CR+PR) will be reported along with a 95% confidence interval. 10.4.4 Safety Analyses Participants will be assessed for toxicity by reporting the grades of toxicity and the type of toxicity observed for all participants, focusing on participants during the phase I evaluation.  
MTD will be determined per section **3.1.2**.  
10.4.5 Baseline Descriptive Statistics Baseline demographic characteristics will be reported. 10.4.6 Planned Interim Analyses In the main phase II cohort, an interim evaluation for efficacy will be performed as described in section **10.2**.  
10.4.7 Exploratory Analyses The following objectives will result in descriptive or comparative analyses when adequate data exist to perform them:  
- To identify pharmacodynamic markers of response including γ H2AX; comparisons between those with and without clinical benefit may be made using an exact Wilcoxon rank sum test;
- To study HRD markers (using whole exome sequencing and RNAseq) and SLFN11 as predictors of response; comparisons between those with and without clinical benefit may be made using an exact Wilcoxon rank sum test.  
- Pharmacokinetics - descriptive analyses only
- Clinical benefit and response rate among participants with extrapulmonary SCLC.  
- Immune subset changes, circulating Tumor DNA: descriptive analyses and comparisons between those with and without clinical benefit may be made using an exact Wilcoxon rank sum test.  
- Any exploratory evaluations which generate quantitative measures will be done using descriptive statistics including confidence intervals when appropriate. Any statistical tests performed for evaluation of exploratory objectives will be done without formal adjustment for multiple comparisons, but in the context of the number of tests performed.  
- To describe the interference of PLX038 with routine coagulation assays
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collaborative agreement 11.1 cooperative research

The CRADA for this protocol has been executed between NCI, NIH and ProLynx (CRADA \#03286).
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11.2 clinical trial agreement (cta)

The CTA for this protocol has been executed between NCI, NIH and Clovis Oncology (CTA \#01141-19).
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human subjects protections 12.1 rationale

No individual who meets the criteria for eligibility will be excluded from participation based on their race, ethnicity, gender, or socioeconomic status. Particular attention will be made to acquire a broad and diversified population.
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12.2 participation of children

Children (younger than 18 years) will not be included in this protocol due to the limited data on study drugs in children and the different biology of childhood malignancy.
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12.3 evaluation of benefits and

The study drugs may help to control the disease. The results may help the investigators learn more about the disease and develop new treatments for participants with this disease.
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12.3.2 risks

12.3.2.1 Study drugs risks All care will be taken to minimize study treatment side effects, but they can be unpredictable in nature and severity. Participants will be examined and evaluated prior to enrollment. All evaluations to monitor the treatment of participants will be recorded in the participant chart. 12.3.2.1.1 PLX038 risks The primary risk to participants participating in this research study is from the toxicity of study drugs. See section **1.2.2** and investigator brochure for full information.  
12.3.2.1.2 Rucaparib risks Table 12. Safety Profile of Rucaparib  
| Rucaparib (N = 1,871)                                                              |                 |               |          |         |
|------------------------------------------------------------------------------------|-----------------|---------------|----------|---------|
| Preferred Terma System Organ Class                                                 | TEAEs           | Serious TEAEs |          |         |
| All Grades                                                                         | CTCAE ≥ Grade 3 |               |          |         |
| n (%)                                                                              | n (%)           | Life               |          |         |
| threatening (CTCAE  grade 4) n (%)                                                 | Fatal n (%)     |               |          |         |
| Blood and Lymphatic System Disorders Anemia/Hemoglobin decreasedb                  | 853 (45.6)      | 474 (25.3)    | 25 (1.3) | 0       |
| Febrile neutropenia                                                                | 19 (1.0)        | 18 (1.0)      | 14 (0.7) | 0       |
| Leukopenia/White blood cell count decreasedb                                       | 179 (9.6)       | 42 (2.2)      | 8 (0.4)  | 0       |
| Lymphopenia/Lymphocyte count decreasedb                                            | 68 (3.6)        | 21 (1.1)      | 4 (0.2)  | 0       |
| Neutropenia and/or low/decreased ANCb                                              | 358 (19.1)      | 183 (9.8)     | 53 (2.8) | 1 (0.1) |
| Thrombocytopenia and/or low/decreased plateletsb                                   | 466 (24.9)      | 129 (6.9)     | 31 (1.7) | 1 (0.1) |
| Gastrointestinal Disorders Diarrhoea                                               | 528 (28.2)      | 29 (1.5)      | 0        | 0       |
| Dyspepsia                                                                          | 188 (10.0)      | 5 (0.3)       | 0        | 0       |
| Nausea                                                                             | 1225 (65.5)     | 64 (3.4)      | 0        | 0       |
| Stomatitis                                                                         | 135 (7.2)       | 4 (0.2)       | 0        | 0       |
| Vomiting                                                                           | 648 (34.6)      | 63 (3.4)      | 0        | 0       |
| General disorders and Administration Site Conditions Asthenia/Fatigueb 1205 (64.4) | 166 (8.9)       | 2 (0.1)       | 0        |         |
| Immune System Disorders Hypersensitivityb                                          | 53 (2.8)        | 0             | 0        | 0       |
| Investigations                                                                     |                 |               |          |         |  
80
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12.3.2 risks

| ALT/AST increasedb                                                                                                                                                                                                                      | 699 (37.4)   | 180 (9.6)   | 2 (0.1)   | 0   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|-------------|-----------|-----|
| Blood creatinine increased                                                                                                                                                                                                              | 321 (17.2)   | 11 (0.6)    | 0         | 0   |
| Metabolism and Nutrition Disorders Decreased appetite                                                                                                                                                                                   | 530 (28.3)   | 28 (1.5)    | 0         | 0   |
| Nervous system disorders Dizziness                                                                                                                                                                                                      | 273 (14.6)   | 2 (0.1)     | 0         | 0   |
| Dysgeusia                                                                                                                                                                                                                               | 421 (22.5)   | 1 (0.1)     | 0         | 0   |
| Respiratory, Thoracic, and Mediastinal Disorders Dyspnoea 297 (15.9)                                                                                                                                                                    | 18 (1.0)     | 0           | 0         |     |
| Skin and subcutaneous tissue disorders Photosensitivity reaction                                                                                                                                                                        | 184 (9.8)    | 3 (0.2)     | 0         | 0   |
| Abbreviations: ADR = adverse drug reaction; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST =  aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; MedDRA = Medical Dictionary for |              |             |           |     |  
Photosensitivity reaction 184 (9.8) 3 (0.2) 0 0  
Abbreviations: ADR = adverse drug reaction; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST =  
aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; TEAE = treatment-emergent adverse event.  
a PTs were based on MedDRA dictionary. If a patient experiences the same PT (System Organ Class) multiple times, then the  
patient will be counted only once for that PT.  
bCombined MedDRA preferred terms.  
Data cut-off for each study: CO-338-010 final data is 16 May 2019; CO-338-017 is 01 February 2019; CO-338-014 is 31 December 2019; CO-338-052 is 13 September 2019; and CO-338-043 is 30 September 2020; and CO-338-087 (ATHENAMONO) is 23 March 2022.
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table 13. serious adverse reactions

| Table 13. Serious Adverse Reactions Considered Expected for Safety Reporting Purposes ADR List Rucaparib  (N = 1,871) System Organ Class Preferred Terma SARs n (%) Blood and Lymphatic System Disorders Anemia/Hemoglobin decreasedb 89 (4.8) Febrile neutropenia 15 (0.8) Leukopenia/White blood cell count decreasedb 3 (0.2) Neutropenia and/or low/decreased ANCb 12 (0.6) Thrombocytopenia and/or low/decreased plateletsb 19 (1.0) Gastrointestinal Disorders Diarrhea 3 (0.2)   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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table 13. serious adverse reactions

| Nausea                                                                                                       | 12 (0.6)   |
|--------------------------------------------------------------------------------------------------------------|------------|
| Vomiting                                                                                                     | 14 (0.7)   |
| General Disorders and Administration Site Conditions Asthenia/Fatigueb                                       | 6 (0.3)    |
| Investigations ALT/AST increasedb                                                                            | 3 (0.2)    |
| Blood creatinine increased                                                                                   | 7 (0.4)    |
| Respiratory, Thoracic, and Mediastinal Disorders Dyspnea                                                     | 3 (0.2)    |
| Abbreviations: ADR = adverse drug reaction; ALT = alanine aminotransferase; ANC = absolute neutrophil count; |            |  
Abbreviations: ADR = adverse drug reaction; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; MedDRA = Medical Dictionary for Regulatory Activities; n = number of patients reporting the event; PT = preferred term; SAR = serious adverse reaction. a PTs were based on MedDRA dictionary.  
b Combined MedDRA preferred terms. There are no expected life-threatening (Grade 4) or fatal (Grade 5) reactions for rucaparib. Data cut-off for each study: CO-338-010 final data is 16 May 2019; CO-338-017 is 01 February 2019; CO-338-014 is 31 December 2019; CO-338-052 is 13 September 2019; CO-338-043 is 30 September 2020; and CO-338087 (ATHENA-MONO) is 23 March 2022.
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12.3.2.2 risk of biopsy

All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection, visceral injury, hematoma and death) that will be explained fully during informed consent. The biopsies will be performed in interventional radiology. 12.3.2.3 Risks of exposure to Ionizing Radiation This research has three optional CT guided biopsies collected for research purposes only and five CT scans per year for disease assessment. Subjects in this study may be exposed to 7.9 rem. This amount is more than would be expected from everyday background radiation. Being exposed to excess radiation can increase the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 0.8 out of 100 (0.8%) and of getting a fatal cancer is 0.4 out of 100 (0.4%).
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12.3.2.4 risks of ct scans

In addition to the radiation risks discussed above, CT scans may include the risks of an allergic reaction to the contrast. Participants might experience hives, itching, headache, difficulty breathing, increased heartrate and swelling. 12.3.2.5 Risks of sedation Biopsies will be done under sedation. Potential side effects of sedation include headache, nausea and drowsiness. These side effects usually go away quickly 12.3.2.6 Research Blood Collection Risks Risks of blood draws include pain and bruising in the area where the needle is placed, lightheadedness, and rarely, fainting and infection. When large amounts of blood are collected, low red blood cell count (anemia) can develop.  
12.3.2.7 Research Hair Follicles Collection Risks Risks of hair follicles collection include light pain and discomfort. 12.3.2.8 Other Risks Risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document or this protocol document. Frequent monitoring for adverse effects will help to minimize the risks associated with administration of the study agents.  
12.3.2.9 Non-Physical Risks of Genetic Research
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risk of receiving unwanted information

Anxiety and stress may arise as a result of the anticipation that unwanted information regarding disease related DNA sequencing or disease tendencies, or misattributed paternity. Participants will be clearly informed that the data related to DNA sequencing and genetic analysis is coded, investigational and will not be shared with participants, family members or health care providers.
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risk related to possibility that

This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency or trait can be released to members of the public, insurers, employers, or law enforcement agencies. Although there are no plans to release results to the participants, family members or health care providers, this risk will be included in the informed consent document. 12.3.3 Assessment of Potential Risks and Benefits Solid tumors treatment needs improved therapy options. Currently running studies suggest that use of PLX038 in combination with rucaparib may have tremendous anti-tumor efficacy. A number of clinically appropriate strategies to minimize risks to participants have been built into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management guidelines. Overall, the potential benefit of the use of PLX038 in combination with rucaparib in subjects with solid tumors outweigh the risks associated with this drug. The potential benefit to a participant that participates in this study is better control of their tumor growth and disease recurrence which may or may not have a favorable impact on symptoms and/or survival. Potential adverse reactions attributable to the administration of the study drugs utilized in this trial are discussed in Sections **1.2.2.3** and **1.2.3.4**. All care will be taken to minimize side effects, but they can be unpredictable in nature and severity.
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12.4 consent process and documentation

The informed consent document will be provided as a physical or electronic document to the participant for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study.  
The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with policy, including HRPP Policy 303) per discretion of the designated study investigator and with the agreement of the participant. Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. Consent will be documented with required signatures on the physical document (which includes the printout of an electronic document sent to participant) or as described below, with a manual
(non-electronic) signature on the electronic document. When required, witness signature will be obtained similarly as described for the investigator and participant. Manual (non-electronic) signature on electronic document: When a manual signature on an electronic document is used for the documentation of consent at the NIH Clinical Center, this study will use the following to obtain the required signatures:  
- Adobe platform (which is not 21 CFR Part 11 compliant); or, - iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the approved consent document on screens at their respective locations (if remote consent); the same screen may be used when in the same location, but is not required. Both the investigator and the participant will sign the document using a finger, stylus or mouse. Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process for additional information (e.g., verification of participant identity when obtaining consent remotely) found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
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regulatory and operational considerations 13.1

This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to study participants, associate investigators, the Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
- Determination of unexpected, significant, or unacceptable risk to participants
- Demonstration of efficacy that would warrant stopping
- Insufficient compliance to protocol requirements
- Data that are not sufficiently complete and/or evaluable
- Determination that the primary endpoint has been met
- Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
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13.2 quality assurance and quality

The clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
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13.3 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the NCI has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
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13.4 confidentiality and privacy

Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. All research activities will be conducted in as private a setting as possible. The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and records required to be maintained by the investigator, including but not limited to, medical records
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such records. The study participant's contact information will be securely stored at the clinical site for internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be stored at the NCI CCR. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by the clinical site(s) and by NCI CCR research staff will be secured and password protected. At the end of the study, all study databases will be archived at the NIH. To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH). This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
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pharmaceutical information 14.1 plx038 (ind

ProLynx LLC will supply investigational PLX038. The PLX038 product was manufactured for Delta-Fly Pharma, Inc as DFP-13318. 14.1.2 Acquisition and Accountability PLX038 will be provided by ProLynx LLC and delivered directly to the NIH Pharmacy. Individual IV bags will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel. IV bags will be delivered from NIH Pharmacy to participant unit where drug will be infused to the participant. 14.1.3 Formulation and Preparation The lyophilized PLX038 (220 mg/vial) can be reconstituted using 11 mL saline or 5% dextrose, then diluted in saline or 5% dextrose IV bags to final volume of 100 mL or 250 mL, respectively. If the volume of the dose to be administered to the participant exceeds 250 mL, PLX038 may be diluted in saline or 5% dextrose IV bags to a final volume of 500 mL.  
14.1.4 Stability and Storage PLX038 lyophilized product should be stored at 2-8 o C.  
14.1.5 Administration Procedures See Section **3.3.1**.  
14.1.6 Toxicity See section **1.2.2.2**.  
Refer to investigator brochure for detailed toxicity information.
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14.2 rucaparib (ind 145310)

14.2.1 Source Investigational supplies of rucaparib will be supplied by Clovis Oncology, Inc 14.2.2 Acquisition and Accountability Rucaparib will be provided by Clovis Oncology, Inc and delivered directly to the NIH Pharmacy. Individual bottles with tablets will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel. Participants will pick up bottles at NIH Pharmacy and will return bottles and not-used tablets after completion of every cycle together with Medication Diary to Study Coordinator. After review of leftover tablets and Medication Diary, unused tablets will be returned to pharmacy and disposed by pharmacy personnel. 14.2.3 Formulation and Preparation The oral formulation of rucaparib contains the camphor sulfonic acid salt of the active agent rucaparib. All dosage strengths are expressed as the weight of free base rucaparib. 14.2.4 How Supplied Rucaparib is currently available as 200 mg, 250 mg, and 300 mg immediate-release tablets for oral administration. All tablets are provided in 60ct high-density polyethylene (HDPE) bottles with child-resistant caps. Tablets should be stored as directed on the product label.  
14.2.5 Administration Please see section **3.3.2**.  
14.2.6 Toxicity See section 1.2.3.4.
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appendices 16.1 appendix a -

| Grade   | Descriptions                                                                                                                                                                                    |
|---------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous                                  |
| 1       | activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |
| 2       | unable to carry out any work activities. Up and about more than 50%  of waking hours.                                                                                                           |
| 3       | In bed >50% of the time. Capable of only limited self-care, confined  to bed or chair more than 50% of waking hours.                                                                            |
| 4       | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                          |
| 5       | Dead.                                                                                                                                                                                           |
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16.2 appendix b - patient's

Cycle Participant's ID
INSTRUCTIONS TO THE PATIENT:
l.  
Complete one form for each cycle of treatment 2.  
You will take rucaparib twice a day for 14 days on and 7 days off during 21-day cycle 3.  
Rucaparib should be taken every 12 hours at approximately the same times each day. Doses should be taken within 2 hours of the scheduled time.  
4.  
In case of a missed dose (more than 2 hours late) or vomiting after taking rucaparib, do not make up the missed dose.  
5. 6.  
Record the date, the number of tablets that you took, and when you took them.  
You may take 8 mg of ondansetron with small meal or snack to prevent nausea and vomiting approximately 30 minutes prior to each dose of rucaparib.  
If you have any comments or notice any side effects, please record them in the comments column.  
7.  
| Please bring this form and your bottles (even it is empty) when you come for your clinic visits.   |                        |                  |                                         |
|----------------------------------------------------------------------------------------------------|------------------------|------------------|-----------------------------------------|
| 8.                                                                                                 | # of Oral Rucaparib    |                  |                                         |
| Tablets taken                                                                                      |                        |                  |                                         |
| Day                                                                                                | Date                   | (every 12 hours) | Comments (side effects or missed doses) |
| AM                                                                                                 | PM                     |                  |                                         |
| l                                                                                                  | Do not take rucaparib. |                  |                                         |
| 2                                                                                                  | Do not take rucaparib. |                  |                                         |
| 3                                                                                                  | Do not take rucaparib. |                  |                                         |
| 4                                                                                                  | Do not take rucaparib. |                  |                                         |
| s                                                                                                  | Do not take rucaparib. |                  |                                         |
| 6                                                                                                  |                        |                  |                                         |
| 7                                                                                                  |                        |                  |                                         |
| 8                                                                                                  |                        |                  |                                         |
| 9                                                                                                  |                        |                  |                                         |
| 10                                                                                                 |                        |                  |                                         |
| 11                                                                                                 |                        |                  |                                         |
| 12                                                                                                 |                        |                  |                                         |  
Version Date: 02/02/2023  
| # of Oral Rucaparib   |                        |                                         |
|-----------------------|------------------------|-----------------------------------------|
| Tablets taken
(every 12 hours)                       |                        |                                         |
| Day                   | Date                   | Comments (side effects or missed doses) |
| AM                    | PM                     |                                         |
| 13                    |                        |                                         |
| 14                    |                        |                                         |
| 15                    |                        |                                         |
| 16                    |                        |                                         |
| 17                    |                        |                                         |
| 18                    |                        |                                         |
| 19                    |                        |                                         |
| 20                    | Do not take rucaparib. |                                         |
| 21                    | Do not take rucaparib. |                                         |  
Participant's signature: