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12.4.1 risks of radiation

The study will involve radiation from the following sources:
Up to 3 CT scans for the collection of biopsies Up to 7 CT scans per year for disease assessment Subjects in this study may be exposed to approximately 10.1 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 1 out of 100 (1%) and of getting a fatal cancer is 0.5 out of 100 (0.5%).  
71 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020 12.4.2 Risk of Treatment: Details of the risk of drug therapy are detailed in section 13. 12.4.3 Blood draws: Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 12.4.4 CT scans: In addition to the radiation risks discussed above, risks associated with CT scans are allergic reaction to and kidney damage from the contrast dye, nausea, vomiting, and anxiety.  
12.4.5 Biopsies: The non-radiation risks associated with the biopsy procedure include pain, swelling and/or bleeding at the biopsy site; infection; and allergic reaction to the local anesthetic used.
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12.5 risks/benefits analysis

This dose and schedule of 105mg/m2 was selected based on the nonclinical PK/PD model, the clinical PK data demonstrating that the LY2606368 systemic exposure at the Maximum Tolerated Dose (MTD) for each schedule of administration is in the range predicted for maximal tumor response, the human PD simulations that predict the average %pChk1 inhibition at the MTD for each schedule of administration achieves the requirements described for the minimum tumor response, the similar safety profile for each schedule, and the increased patient convenience.  
Adult subjects: More than minimal risk and the prospect of direct benefit.  
Adults unable to consent: Category B - Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.  
Protocol Specific Justification for Risk Assessment: For adults who lose the capacity to consent the risk is greater than minimal due to the potential toxicities of treatment, but there is prospect for direct benefit due to the potential for reduction of tumor burden.
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12.6 consent process and documentation

The informed consent document will be provided to the participant or consent designee(s) as applicable 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 72 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020 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) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed.
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12.6.1 consent process for adults

For participants addressed in section **12.3**, an LAR will be identified consistent with Policy 403 and informed consent obtained from the LAR, as described in Section 12.6.
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13 regulatory and operational considerations

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, investigator, funding agency, 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 the 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 the 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 73 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020 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

Each 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 National Cancer Institute 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/each 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 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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14 pharmaceutical information 14.1 ly2606368

LY2606368 is an investigational agent (IND \#123172) and will be supplied to the NIH Clinical Center by Eli Lilly and Company (Indianapolis, IN).
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14.1.2 toxicity

As of 04 April 2016, data were available from 210 patients who were treated with LY2606368 on Schedule 1 or 2. PK data are available from 194 patients from 3 ongoing clinical trials (studies JTJA, JTJF, and JTJK). Study JTJA is the first-in-human phase 1 study of LY2606368. Hematologic Toxicity Neutropenia is the most frequent toxicity in study JTJA and has been observed at all doses and schedules of LY2606368. Prophylactic granulocyte colony stimulating factor (G-CSF) use is permitted as indicated in **3.3.1.1.** Non-Hematologic Toxicity The only non-hematologic treatment-emergent AEs (TEAEs) occurring in greater than 10% of patients and deemed by the investigators to be related to LY2606368 treatment (combined Schedule 1 and Schedule 2) were nausea (15%, grade 1: 14%, grade 2: 1%) and fatigue (29%, grade 1/2: 27%, grade 3: 2%). Related non-hematologic TEAEs occurring in 5% to 10% of patients included: anorexia (8%), headache (7%), oral mucositis (7%), diarrhea (5%), and vomiting (5%). All of these were grade 1 or 2. Cardiovascular Effects Please see **3.3.2** QTc Prolongation.  
No corrected QT interval (QTc) prolongation was observed in dogs at doses up to 10 mg/kg (200 mg/m2). The mean maximum plasma concentration (Cmax) levels at the dose at which QTc prolongation was seen in dogs (6950 and 5862 ng/mL at 40 mg/kg, or 800 76 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020 mg/m2, given as a 1- or 2-hour infusion, respectively) are significantly greater than the largest mean LY2606368 Cmax in humans at the MTD of 40 mg/m2 administered on days 1 to 3 every 14 days (Schedule 1) (cohort mean = 347 ng/mL on day 3 of cycle 1 from Part A
in the current phase I study [dose escalation]), and the largest mean LY2606368 Cmax in humans at the MTD of 105 mg/m2 administered on day 1 every 14 days (cohort mean = 867 ng/mL on day 1 of cycle 2 from Part A in the current phase I study). As of April 2016, in study JTJA (LY2606368 monotherapy), no prolongations in average QTcF interval to >480 ms or of > 60 ms from baseline were observed with LY2606368 monotherapy (n=101) at any time point. Eight patients (7.9%) had a QTcF change of > 30 ms from baseline. None of these changes exceeded 39 ms, and none were observed to be associated with AEs. In study JTJK
(LY2606368 monotherapy in Japanese patients), two of 10 patients had grade 2 QTcF prolongation (both were on 80mg/m2; one with baseline QTcF 468 ms, changed to post-treatment QTcF 511 ms with grade 1 atrial fibrillation, and no known history of cardiovascular issues and normal electrolytes, deemed DLT; another with baseline QTcF 432 ms but had nonspecific T wave changes, precluding accurate measurement of the QT interval. No other cardiac AEs were reported for these patients. A thorough QTc study has not yet been conducted to date for Japanese patients. On days when LY2606368 is administered, patients should avoid taking any concomitant medications within 12 hours before and after the infusion of LY2606368 that are known or suspected to cause prolonged QTc or Torsades de Points and, if possible, alternative agents should be considered. Because LY2606368 interacts with multiple 5-hydroxytryptamine (5-HT) receptors, patients should be monitored closely for any signs and symptoms of serotonin syndrome. If observed, appropriate treatment (eg, cyproheptadine or octreotide) may be used as a treatment. Additional findings in animals that also may occur in humans at clinically relevant doses include abnormal stools, skin reddening, decreased body weight and/or food consumption, and tremors. In addition, 8 of 20 dogs given doses of LY2606368 above the MTD were sacrificed for humane reasons prior to scheduled termination. The primary clinical signs associated with the declining condition of these animals were consistent with gastrointestinal (GI) injury and dehydration. Experience with concurrent radiation therapy (RT) and LY2606368 There is an ongoing study with LY2606368 in combination with either cisplatin/RT or cetuximab/RT in patients with locally advanced HNSCC
(study JTJI). As of August 2017, 19 patients have been dosed at LY2606368 doses of 20 mg/m2 or 40 mg/m2 in combination with IMRT - 2.0 Gy/day fractions (daily x 5 for 7 weeks)- LY2606368 is still given biweekly. Validated data is available from 14 patients (Study JTJI, **Table 7** and 77 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020 below). The toxicities have been consistent with either radiation, LY2606368, or cetuximab/cisplatin. During palliative radiation, a break in LY2606368 therapy is allowed not to overlap the therapies. Currently, the estimated median terminal half-life of LY2606368 is 27 hours.  
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| I4D-MC-JTJI                           | Prexasertib with  Cisplatin and  Radiation (N=7) n (%)   | Prexasertib with  Cetuximab and  Radiation (N=7) n (%)   | Total (N=14) n (%)   |             |           |          |
|---------------------------------------|----------------------------------------------------------|----------------------------------------------------------|----------------------|-------------|-----------|----------|
| Preferred Term                        | All Grades                                               | Grade 3/4/5 All Grades Grade 3/4/5                       | All Grades           | Grade 3/4/5 |           |          |
| Radiation skin injury                 | 5 (71.4)                                                 | 0                                                        | 6 (85.7)             | 2 (28.6)    | 11 (78.6) | 2 (14.3) |
| Anaemia                               | 5 (71.4)                                                 | 1 (14.3)                                                 | 4 (57.1)             | 0           | 9 (64.3)  | 1 (7.1)  |
| Dry mouth                             | 4 (57.1)                                                 | 0                                                        | 5 (71.4)             | 0           | 9 (64.3)  | 0        |
| Stomatitis                            | 3 (42.9)                                                 | 2 (28.6)                                                 | 6 (85.7)             | 4 (57.1)    | 9 (64.3)  | 6 (42.9) |
| Platelet count decreased              | 6 (85.7)                                                 | 0                                                        | 3 (42.9)             | 0           | 9 (64.3)  | 0        |
| Neutrophil count decreased            | 6 (85.7)                                                 | 5 (71.4)                                                 | 2 (28.6)             | 2 (28.6)    | 8 (57.1)  | 7 (50.0) |
| Dysphagia                             | 3 (42.9)                                                 | 1 (14.3)                                                 | 4 (57.1)             | 2 (28.6)    | 7 (50.0)  | 3 (21.4) |
| Weight decreased                      | 2 (28.6)                                                 | 0                                                        | 5 (71.4)             | 0           | 7 (50.0)  | 0        |
| Nausea                                | 4 (57.1)                                                 | 0                                                        | 2 (28.6)             | 0           | 6 (42.9)  | 0        |
| Dermatitis acneiform                  | 0                                                        | 0                                                        | 5 (71.4)             | 4 (57.1)    | 5 (35.7)  | 4 (28.6) |
| Febrile neutropenia                   | 3 (42.9)                                                 | 1 (14.3)                                                 | 1 (14.3)             | 1 (14.3)    | 4 (28.6)  | 2 (14.3) |
| Sinus tachycardia                     | 2 (28.6)                                                 | 0                                                        | 2 (28.6)             | 0           | 4 (28.6)  | 0        |
| Hyponatraemia                         | 3 (42.9)                                                 | 1 (14.3)                                                 | 1 (14.3)             | 0           | 4 (28.6)  | 1 (7.1)  |
| Aphasia                               | 2 (28.6)                                                 | 2 (28.6)                                                 | 2 (28.6)             | 1 (14.3)    | 4 (28.6)  | 3 (21.4) |
| Vomiting                              | 3 (42.9)                                                 | 0                                                        | 1 (14.3)             | 0           | 4 (28.6)  | 0        |
| Fatigue                               | 2 (28.6)                                                 | 0                                                        | 2 (28.6)             | 0           | 4 (28.6)  | 0        |
| Mucosal infection                     | 2 (28.6)                                                 | 0                                                        | 2 (28.6)             | 0           | 4 (28.6)  | 0        |
| Alanine aminotransferase  increased   | 2 (28.6)                                                 | 0                                                        | 2 (28.6)             | 0           | 4 (28.6)  | 0        |
| Aspartate aminotransferase  increased | 2 (28.6)                                                 | 0                                                        | 2 (28.6)             | 0           | 4 (28.6)  | 0        |
| Blood creatinine increased            | 2 (28.6)                                                 | 0                                                        | 1 (14.3)             | 0           | 3 (21.4)  | 0        |  
| Prexasertib with  Cisplatin and  Radiation (N=7) n (%)                                       | Prexasertib with  Cetuximab and  Radiation (N=7) n (%)   | Total (N=14) n (%)                 |            |             |          |    |
|----------------------------------------------------------------------------------------------|----------------------------------------------------------|------------------------------------|------------|-------------|----------|----|
| Preferred Term                                                                               | All Grades                                               | Grade 3/4/5 All Grades Grade 3/4/5 | All Grades | Grade 3/4/5 |          |    |
| White blood cell count                                                                       | 0                                                        | 1 (14.3)                           | 0          | 3 (21.4)    | 0        |    |
| 2 (28.6)                                                                                     |                                                          |                                    |            |             |          |    |
| decreased Tinnitus                                                                           | 2 (28.6)                                                 | 0                                  | 0          | 0           | 2 (14.3) | 0  |
| Lymphocyte count decreased                                                                   | 2 (28.6)                                                 | 0                                  | 0          | 0           | 2 (14.3) | 0  |
| Dyspepsia                                                                                    | 0                                                        | 0                                  | 2 (28.6)   | 0           | 2 (14.3) | 0  |
| Infusion related reaction                                                                    | 0                                                        | 0                                  | 2 (28.6)   | 0           | 2 (14.3) | 0  |
| Headache                                                                                     | 0                                                        | 0                                  | 2 (28.6)   | 0           | 2 (14.3) | 0  |
| Source: /lillyce/prd/ly2606368/cibjan2017/output/i4d_mc_jtji/smteaeptsoc and smteaeptsocmax. |                                                          |                                    |            |             |          |    |
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14.1.3 formulation and preparation

The drug product, LY2606368 for injection, is supplied for clinical trial use as a lyophilized, yellow to white solid, in glass vials and is composed of LY2606368 mesylate monohydrate and the inactive ingredient Captisol®. Each vial contains 20 mg or 40 mg of the base compound LY2606368. The vial contains a 5% excess to facilitate the withdrawal of the label amount, 20 mg/vial or 40 mg/vial for application with an appropriate device, such as an infusion set. LY2606368 will be infused through a low-sorbing, polyolefin-lined administration set with in-line 0.2-micrometer polyethersulfone filter. All components must be DEHP-free.  
Patients will receive LY2606368 at the RP2D of 105 mg/m2 IV once every 14 days of a 28-day cycle.  
Reconstituting the vial contents with 10 mL of water gives a clear yellow solution with a concentration of 2 mg/mL of LY2606368, pH 4 to 7, and an osmotic pressure ratio of 344 mOsm.  
80 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020
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14.1.4 stability and storage

The drug product is stable when stored at room temperature. The reconstituted formulation is stable for at least 24 hours at room temperature; however, since the reconstituted drug product does not contain a preservative, the unused solution must be discarded after 12 hours.
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14.1.5 administration procedures

LY2606368 dose MAY be recalculated during repeated treatment cycles as a function of minor changes in body weight measurements through time. Dose recalculation during repeated treatment cycles is REQUIRED only when a patient's weight changes +/- 10% or more from their body weight measured just before starting study treatment (baseline weight). LY2606368 is administered as an IV infusion over 1hour (+/-10min) using a central or free flowing peripheral IV line with an appropriate filter. Subsequent infusion may be extended if infusion over 1hr was not well tolerated, including but not limited to grade 1 facial flushing. LY2606368 should not come in contact with normal saline. The patient's vascular access device should be flushed with dextrose 5% injection (D5W) before and after LY2606368 administration. The reconstituted drug product from the vials should be diluted with Dextrose 5% Injection (D5W) to a final volume of no more than 250 ml. If less than 250 ml is used, the concentration of LY2606368 must be maintained within a range of 0.08 mg/mL to 1.60 mg/mL of LY2606368.
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14.1.6 incompatibilities

LY2606368 is incompatible with solutions containing saline or lactated Ringer and must not be mixed or administered simultaneously with other drugs through the same infusion line.  
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15 references

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6. Safra T, Borgato L, Nicoletto MO, et al. BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Molecular cancer therapeutics 2011;10:2000-7.  
7. Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutationpositive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012;30:2654-63. 8. Long KC, Kauff ND. Hereditary ovarian cancer: recent molecular insights and their impact on screening strategies. Current opinion in oncology 2011;23:526-30. 9. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proceedings of the National Academy of Sciences of the United States of America 2011;108:18032-7. 10. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer research 2006;66:8109-15. 11. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:3555-61. 12. Carrassa L, Damia G. Unleashing Chk1 in cancer therapy. Cell Cycle 2011;10:2121-8. 13. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215-28. 14. Beltran H, Yelensky R, Frampton GM, et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. European urology 2013;63:920-6.  
15. Dai Y, Grant S. Targeting Chk1 in the replicative stress response. Cell Cycle 2010;9:1025.  
16. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70. 17. Ma CX, Janetka JW, Piwnica-Worms H. Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics. Trends in molecular medicine 2011;17:88-96. 18. Maya-Mendoza A, Petermann E, Gillespie DA, Caldecott KW, Jackson DA. Chk1 regulates the density of active replication origins during the vertebrate S phase. The EMBO journal 2007;26:2719-31. 19. Bucher N, Britten CD. G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. British journal of cancer 2008;98:523-8. 20. Zachos G, Black EJ, Walker M, et al. Chk1 is required for spindle checkpoint function. Developmental cell 2007;12:247-60. 21. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-21. 22. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose)
polymerase. Nature 2005;434:913-7.  
23. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The New England journal of medicine 2009;361:123-34. 24. Deng CX. BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic acids research 2006;34:1416-26. 25. Ashwell S, Zabludoff S. DNA damage detection and repair pathways--recent advances with inhibitors of checkpoint kinases in cancer therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2008;14:4032-7. 26. Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nature genetics 2002;30:285-9. 27. Samuel C. McNeely TFB, Sara DurlandBusbice, Darlene S. Barnard, Mark S. Marshall, Aimee K. Bence, Richard P. Beckmann. LY2606368, a second generation Chk1 inhibitor, inhibits growth of ovarian carcinoma xenografts either as monotherapy or in combination with standard-of-care agents. Molecular cancer therapeutics 2011;10:Supplement 1; abstr A108. 28. Turner NC, Reis-Filho JS, Russell AM, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 2007;26:2126-32. 29. Deeb KK, Michalowska AM, Yoon CY, et al. Identification of an integrated SV40 T/t-antigen cancer signature in aggressive human breast, prostate, and lung carcinomas with poor prognosis. Cancer research 2007;67:8065-80. 30. Neve RM, Chin K, Fridlyand J, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 2006;10:515-27. 31. Bennett CN, Tomlinson CC, Michalowski AM, et al. Cross-species genomic and functional analyses identify a combination therapy using a CHK1 inhibitor and a ribonucleotide reductase inhibitor to treat triple-negative breast cancer. Breast Cancer Res 2012;14:R109.  
32. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006;24:3187-205. 33. Patch AM, Christie EL, Etemadmoghadam D, et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 2015;521:489-94. 34. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2014;32:1302-8. 35. Hong D, Infante J, Janku F, et al. Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016;34:1764-71. 36. Scher HI, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of Clinical Oncology 2008;26:1148-59. 37. Hsu S, Kim M, Hernandez L, et al. IKK-epsilon coordinates invasion and metastasis of ovarian cancer. Cancer research 2012;72:5494-504. 38. Pecot CV, Bischoff FZ, Mayer JA, et al. A novel platform for detection of CK+ and CK- CTCs. Cancer discovery 2011;1:5806. 39. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 40. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1999;17:3461-7. 41. Sonpavde G, Fleming MT, Hutson TE, Galsky MD. Trial design for metastatic castration-resistant prostate cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008;26:3647-8; author reply 8-9. 42. Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. Journal of the National Cancer Institute 2000;92:1534-5. 43. Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). Journal of the National Cancer Institute 2004;96:487-8.  
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16 appendices

16.1 APPENDIX A - PERFORMANCE STATUS C**RITERIA**  
| ECOG Performance Status Scale      | Karnofsky Performance Scale                                                                                            |                                                                            |                                                                         |
|------------------------------------|------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|-------------------------------------------------------------------------|
| Grade                              | Descriptions                                                                                                           | Percent                                                                    | Description                                                             |
| 100                                | Normal, no complaints, no  evidence of disease.                                                                        |                                                                            |                                                                         |
| 0                                  | Normal activity. Fully active,  able to carry on all pre-disease  performance without restriction.                     | 90                                                                         | Able to carry on normal activity;  minor signs or symptoms of  disease. |
| Symptoms, but ambulatory.          | Normal activity with effort;  some signs or symptoms of                                                                |                                                                            |                                                                         |
| Restricted in physically strenuous | disease.                                                                                                               |                                                                            |                                                                         |
| 1                                  | activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light                      | 70                                                                         |                                                                         |
| housework, office work).           | 80                                                                                                                     | Cares for self, unable to carry on  normal activity or to do active  work. |                                                                         |
| In bed <50% of the time.           | Requires occasional assistance,                                                                                        |                                                                            |                                                                         |
| Ambulatory and capable of all      | but is able to care for most of  his/her needs.                                                                        |                                                                            |                                                                         |
| 2                                  | self-care, but unable to carry out  any work activities. Up and  about more than 50% of waking  hours.                 | 60                                                                         | Requires considerable assistance  and frequent medical care.            |
| 50 40                              | Disabled, requires special care  and assistance.                                                                       |                                                                            |                                                                         |
| 3                                  | In bed >50% of the time.  Capable of only limited self-care,  confined to bed or chair more  than 50% of waking hours. | 30                                                                         | Severely disabled,  hospitalization indicated. Death  not imminent.     |  
85 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020  
| 100% bedridden. Completely   | 20                                                                           | Very sick, hospitalization  indicated. Death not imminent.   |                                                 |
|------------------------------|------------------------------------------------------------------------------|--------------------------------------------------------------|-------------------------------------------------|
| 4                            | disabled. Cannot carry on any  self-care. Totally confined to bed  or chair. | 10                                                           | Moribund, fatal processes  progressing rapidly. |
| 5                            | Dead.                                                                        | 0                                                            | Dead.                                           |  
86  
Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020  
| Generic Name                                                                                                                                              | Brand Names                              | Drug Class            | Therapeutic Use Abnormal heart    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------|-----------------------|-----------------------------------|
| Amiodarone                                                                                                                                                | Cordarone®, Pacerone®, Nexterone®        | Anti-arrhythmic       | rhythm                            |
| Phosphodiesterase 3                                                                                                                                       |                                          |                       |                                   |
| Anagrelide                                                                                                                                                | Agrylin®, Xagrid®                        | inhibitor             | Thrombocythemia                   |
| Arsenic trioxide                                                                                                                                          | Trisenox®                                | Anti-cancer           | Leukemia                          |
| Azithromycin                                                                                                                                              | Zithromax®, Zmax®                        | Antibiotic            | Bacterial infection               |
| Chloroquine                                                                                                                                               | Aralen®                                  | Anti-malarial         | Malaria infection                 |
| Anti-psychotic / Antiemetic                                                                                                                                                           | Schizophrenia/                           |                       |                                   |
| Chlorpromazine                                                                                                                                            | Thorazine®, Largactil®, Megaphen®        | nausea                |                                   |
| Citalopram                                                                                                                                                | Celexa®, Cipramil®                       | Anti-depressant, SSRI | Depression                        |
| Clarithromycin                                                                                                                                            | Biaxin®, Prevpac®                        | Antibiotic            | Bacterial infection               |
| Cocaine                                                                                                                                                   | Cocaine                                  | Local anesthetic      | Topical anesthetic Abnormal heart |
| Disopyramide                                                                                                                                              | Norpace®                                 | Anti-arrhythmic       | rhythm Abnormal heart             |
| Dofetilide                                                                                                                                                | Tikosyn®                                 | Anti-arrhythmic       | rhythm                            |
| Dronedarone                                                                                                                                               | Multaq®                                  | Anti-arrhythmic       | Atrial Fibrillation               |
| Anti-psychotic / Antiemetic                                                                                                                                                           | Anesthesia adjunct,                      |                       |                                   |
| Droperidol                                                                                                                                                | Inapsine®, Droleptan®, Dridol®, Xomolix® | nausea                |                                   |
| EES®, MY-E®, Robimycin®, EMycin®,  Erymax®, Ery-Tab®, Eryc Ranbaxy®,  Erypar®, Eryped®, Erythrocin Stearate  Filmtab®, Erythrocot®, E-Base®, Erythroped®, | Bacterial infection;                     |                       |                                   |
| Ilosone®, Pediamycin®, Zineryt®, Abboticin®,                                                                                                              | Antibiotic                               | increase GI motility  |                                   |
| Erythromycin                                                                                                                                              |                                          |                       |                                   |  
16.2 APPENDIX B - DRUGS KNOWN TO CAUSE QT PROLONGATION AND/**OR INDUCE TORSADES DE POINTES**  
| Abboticin-ES®, Erycin®, PCE Dispertab®,  Stiemycine®, Acnasol®, Tiloryth® Cipralex®, Lexapro®, Nexito®, Seroplex®,  Elicea®, Lexamil®, Lexam®, [Anxiset-E®,  Exodus®, Esto®, Entact®, Losita®, Reposil®,  Animaxen®, Esitalo®, Lexamil® (Not available   | Major depression/                         |                   |                     |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|-------------------|---------------------|
| in the US)]                                                                                                                                                                                                                                              | Anti-depressant, SSRI                     | Anxiety disorders |                     |
| Generic Name                                                                                                                                                                                                                                             | Brand Names                               | Drug Class        | Therapeutic Use     |
| Escitalopram                                                                                                                                                                                                                                             | Tambocor®, Almarytm®, Apocard®, Ecrinal®, | Abnormal heart    |                     |
| Flecainide                                                                                                                                                                                                                                               | Flécaine®                                 | Anti-arrhythmic   | rhythm              |
| Halofantrine                                                                                                                                                                                                                                             | Halfan®                                   | Anti-malarial     | Malaria infection   |
| Aloperidin®, Bioperidolo®, Brotopon®,  Dozic®, Einalon S®, Eukystol®, Halosten®,  Keselan®, Linton®, Peluces®, Serenace®,  Serenase®, Sigaperidol®, Haldol® (US & UK),                                                                                   | Schizophrenia,                            |                   |                     |
| Duraperidol® (Germany),                                                                                                                                                                                                                                  | Anti-psychotic                            | agitation         |                     |
| Haloperidol                                                                                                                                                                                                                                              | Abnormal heart                            |                   |                     |
| Ibutilide                                                                                                                                                                                                                                                | Corvert®                                  | Anti-arrhythmic   | rhythm              |
| Dolophine®, Symoron®, Amidone®,                                                                                                                                                                                                                          | Pain control,                             |                   |                     |
| Methadone                                                                                                                                                                                                                                                | Methadose®, Physeptone®, Heptadon®        | Opiate            | narcotic dependence |
| Moxifloxacin                                                                                                                                                                                                                                             | Avelox®, Avalox®, Avelon®                 | Antibiotic        | Bacterial infection |
| Zofran®, Anset®, Ondemet®, Zuplenz®,  Emetron®, Ondavell®, Emeset®, Ondisolv®,  Setronax®                                                                                                                                                                | Anti-emetic                               | Nausea, vomiting  |                     |
| Ondansetron                                                                                                                                                                                                                                              | Pneumocystis                              |                   |                     |
| Pentamidine                                                                                                                                                                                                                                              | NebuPent®, Pentam®                        | Antibiotic        | pneumonia           |
| Pimozide                                                                                                                                                                                                                                                 | Orap®                                     | Anti-psychotic    | Tourette's tics     |
| Procainamide  (Oral off US                                                                                                                                                                                                                               | Abnormal heart                            |                   |                     |
| mkt)                                                                                                                                                                                                                                                     | Pronestyl®, Procan®                       | Anti-arrhythmic   | rhythm              |
| Quinaglute®, Duraquin®, Quinact®,                                                                                                                                                                                                                        | Abnormal heart                            |                   |                     |
| Quinidine                                                                                                                                                                                                                                                | Quinidex®, Cin-Quin®, Quinora®            | Anti-arrhythmic   | rhythm              |  
88  
Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020  
| Sevoflurane                                     | Ulane®, Sojourn®                   | Anesthetic, general   | Anesthesia Abnormal heart   |
|-------------------------------------------------|------------------------------------|-----------------------|-----------------------------|
| Sotalol                                         | Betapace®, Sotalex®, Sotacor®      | Anti-arrhythmic       | rhythm                      |
| Thioridazine                                    | Mellaril®, Novoridazine®, Thioril® | Anti-psychotic        | Schizophrenia               |
| Vandetanib                                      | Caprelsa®                          | Anti-cancer           | Thyroid cancer              |
| Source: www.QTdrugs.org Updated September 2013. |                                    |                       |                             |  
89 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020 16.3 APPENDIX C - LABORATORY STANDARD OPERATING PROCEDURE- TISSUE CORE COLLECTION
Lee Laboratory Standard Operating Procedure for Tissue Core CollectionNeedle Biopsy - Cryopreservation in OCT
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principle

Core needle biopsies are used to sample tissue from a specific, defined location. These biopsies may consist of normal, pre-malignant and malignant tissue due to the multi-level tissue sample that is obtained. This type of sample is ideal for studying the micro-tumor environment. Rapid freezing of the sample is required to prevent degradation of the proteins or RNA. Optimal Cutting Temperature (OCT) compound is an alcohol polymer that is liquid at room temperature and a solid at –20oC. This polymer is used to cryo-protect the tissue and provide a medium for cryo-sectioning.
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materials

Cryomolds (Sakura Finetek Ca.t \# 4728) OCT (Sakura Finetek Cat. \# 4583) Dry ice Ultra cold freezer (-700 to -800C) Needle: 16 or 18 gauge Permanent marker Sterile forceps Sterile Glass slides Aluminum foil or 50ml Falcon tubes
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procedure

1. Prepare all supplies prior to the biopsy procedure to avoid delay once the specimen has been obtained. 2. Label the handle and the front surface of the cryomold with the sample or participant's identifying information. 3. Perform core needle biopsy. 4. Pick the core from the biopsy needle onto a sterile glass slide. 5. Fill cryomold about 1/3 full with OCT. Place the cryomold in dry ice to partially freeze the OCT. The OCT should be jelly-like, not completely frozen. 6. Carefully lift the core biopsy by both ends with sterile forceps. Do not stretch the biopsy or it will break.  
90 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020 7. Lay the biopsy as straight as possible in the OCT. Once the sample touches the OCT, you cannot reposition it or the sample will break apart.  
8. Quickly add OCT on top of the biopsy, completely covering the sample.  
9. Ensure the sample is level and freeze immediately in dry ice.  
10. Store wrapped in aluminum foil or in a 50ml Falcon tube at –70oC.  
Note: Do not lay the biopsy on frozen OCT and cover it with liquid OCT. The OCT will not fuse and will split into two sections when cutting the frozen tissue sections.
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frozen section slides

1. Frozen sections for proteomic analysis should be cut at 5-8um on plain, uncoated glass microscope slides. 2. The tissue section should be placed as close as possible to the center of the slide. Do not place the frozen section at the end of the slide. 3. Two tissue sections from the same biopsy may be placed on the same glass slide if space permits.  
4. Do not allow the tissue section to air on the slide. Freeze immediately on dry ice or at –80oC.  
91 Abbreviated Title: LY Chk1/2 Inhibitor Amendment Version Date: 12/02/2020 16.4 APPENDIX D - HEREDITARY BREAST/OVARIAN CANCER SYNDROME FAMILY HISTORY CRITERIA (MODIFIED FROM **NCCN,**
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2013)

Personal history of **breast cancer** AND one or more of the following:
A family member with a known deleterious BRCA1 or *BRCA2* mutation. Diagnosed <50 with > 1 first, second, or third degree relative with invasive breast cancer and/or ductal carcinoma in situ diagnosed at any age.  
Diagnosed at any age with > 1 first, second, or third degree relative with invasive breast cancer and/or ductal carcinoma in situ
<50.  
Diagnosed at any age with > 2 first, second, or third degree relative with invasive breast cancer and/or ductal carcinoma in situ diagnosed at any age.  
Diagnosed at any age with > 1 first, second, or third degree relative with epithelial ovarian cancer diagnosed at any age.  
Diagnosed at any age with > 2 first, second, or third degree relative with pancreatic cancer and/or aggressive prostate cancer
(Gleason score >7) diagnosed at any age.  
> 1 first, second, or third degree MALE relative with invasive breast cancer and/or ductal carcinoma in situ diagnosed at any age.  
Individual ethnicity associated with higher mutation frequency (i.e. Ashkenazi Jewish).  
Personal history of **ovarian cancer** AND one or more of the following:
A family member with a known deleterious BRCA1 or *BRCA2* mutation. > 1 first, second, or third degree relative with invasive breast cancer and/or ductal carcinoma in situ diagnosed at any age. > 2 first, second, or third degree relative with pancreatic cancer and/or aggressive prostate cancer (Gleason score >7)
diagnosed at any age.  
> 1 first, second, or third degree MALE relative with invasive breast cancer and/or ductal carcinoma in situ diagnosed at any age.  
Individual ethnicity associated with higher mutation frequency (i.e. Ashkenazi Jewish).
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reference

NCCN, (2013). Genetic/familial high-risk assessment: Breast and ovarian. Version 4.2013. NCCN.org