Clinical trial NCT04209595
Conditions: Small Cell Lung Cancer Extra-Pulmonary Small Cell Carcinomas
Keywords: PARP Inhibitor Chemotherapy DDR Inhibitor
Sponsor: National Cancer Institute (NCI)
Start date: 2020-04-08; Completion date: 2025-02-24
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

Drugs known as poly-adenosine diphosphate ribose polymerase (PARP) inhibitors are known to help stop tumor growth in patients with breast, ovarian cancers and many other cancers including prostate and pancreatic cancers. Many research studies done in animals and human cells have shown that these types of drugs can improve how well chemotherapy works. Standard chemotherapy can be too toxic to be combined with PARP inhibitors. In this study, we use a new form of chemotherapy called PLX038 (PEGylated SN38) to see if it can be safely combined with PARP inhibitors to shrink tumors.

Objective:

To find a safe combination of PLX038 and rucaparib, and to see if this mix will cause tumors to shrink.

Eligibility:

People age 18 and older with solid tumors, small cell lung cancer (SCLC), or small cell cancer outside their lungs.

Design:

Participants will be screened with:

Physical exam

Blood tests

Records of their diagnosis (or they will have a tumor biopsy).

A review of their symptoms and medications.

A review of their ability to perform their normal activities.

Electrocardiograms, to measure the electrical activity of the heart.

Computed tomography (CT) scans of the chest, abdomen, and pelvis. CT scans are a series of X-rays.

Participants will get PLX038 by intravenous catheter on Day 1 of each cycle (1 cycle = 21 days). For this, a small plastic tube is put into an arm vein. They will take rucaparib twice daily by mouth on Days 3 to 19 of each cycle. They will keep a medicine diary.

Participants may give a hair sample. They may have optional tumor biopsies.

Screening tests are repeated throughout the study.

About 30 days after treatment ends, participants will have a safety follow-up visit. They will give blood samples, talk about their health, and get a physical exam. Then they will be called or emailed every 6 months....

Detailed description:
Background:

* We hypothesize that a dose-escalation strategy that incorporates tumor targeted deoxyribonucleic acid (DNA)-damaging chemotherapy and DNA-damage response (DDR) inhibitors could allow safe and effective administration of DNA damage response (DDR) inhibitor-chemotherapy combination.
* PLX038 is a PEGylated conjugate of SN38 with improved properties including increased solubility, higher exposure and longer half-life. SN-38 is the active metabolite of CPT-11 (irinotecan) that inhibits topoisomerase 1 (Top1) and causes DNA strand breakage. As a specific DNA damaging agent, SN-38 enhances cell kill in tumors deficient in the DNA-damage response and when combined with inhibitors of the DDR.
* Rucaparib is a potent oral poly ADP ribose polymerase (PARP) inhibitor that is approved for the maintenance treatment of participants with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
* We hypothesize that the combination of PLX038 plus rucaparib is more efficacious than either agent alone.

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 participants with small cell lung cancer and extra-pulmonary small cell carcinomas.

Eligibility:

* Subjects with histologically confirmed solid tumors (Phase I) OR histologically or cytologically confirmed small cell lung cancer (SCLC) (Phase II) OR histologically or cytologically confirmed extra-pulmonary small cell carcinomas (Phase II).
* Age greater than or equal to 18 years
* Subjects must have evaluable, or measurable disease.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Adequate organ function

Design:

* This is an open label Phase I/II trial accruing initially one cohort to determine maximum tolerated dose (MTD) of combined treatment of PLX038 and rucaparib (Phase I); and to examine the safety and efficacy of PLX038 in combination with rucaparib in the following cohort (Phase II).
* PLX038 will be administered by intravenous (IV) infusion on day 1 of every 21-days cycle, rucaparib will be administered by mouth (PO) twice daily on days 6 to 19 of every cycle.
* Treatment will continue until progression or unacceptable toxicity.
* Biomarkers of participant response to treatment will be investigated in an exploratory manner pre- and post-treatment.

Arms: arm 1: Phase I - Participants with solid tumors enrolled to PLX038 (PEGylated SN38) and rucaparib escalation dose levels.

PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 200 mg by mouth (PO) arm 2: Phase I - Participants with solid tumors enrolled to PLX038 (PEGylated SN38) and rucaparib escalation dose levels.

PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 400 mg by mouth (PO) arm 3: Phase I Participants with solid tumors enrolled to PLX038 (PEGylated SN38) and rucaparib escalation dose levels.

PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 300 mg by mouth (PO) arm 4: Phase IIA Participants with small cell lung cancer (SCLC) enrolled at the maximum tolerated dose (MTD) of PLX038 (PEGylated SN38) and rucaparib after the MTD of PLX038 and rucaparib is established.

Level 2, PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 3, PLX038, every 3 weeks, 1.7 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 4, PLX038, every 3 weeks, 2.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 2A PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 400 mg by mouth (PO); and/or Level 3A. PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 600 mg by mouth (PO). arm 5: Phase IIB Participants with extra-pulmonary small cell carcinomas enrolled at the maximum tolerated dose (MTD) of PLX038 (PEGylated SN38) and rucaparib after the MTD of PLX038 and rucaparib is established.

Level 2, PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 3, PLX038, every 3 weeks, 1.7 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 4, PLX038, every 3 weeks, 2.3 g/m\^2, intravenous (IV); Rucaparib, days 3-19 twice a day (BID), total dose, 600 mg by mouth (PO); Level 2A PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 400 mg by mouth (PO); and/or Level 3A. PLX038, every 3 weeks, 1.3 g/m\^2, intravenous (IV); Rucaparib, days 5-19 twice a day (BID), total dose, 600 mg by mouth (PO).
Interventions: intervention 1: PLX038 intervention 2: Rucaparib intervention 3: Ondansetron
Intervention descriptions: intervention 1: Phase I: Dose escalation will follow the classical 3+3 trial design by Fibonacci sequence. Phase II: Maximum tolerated dose (MTD) identified in phase I. PLX038 (PEGylated SN38) will be administered as a 1 hour (-10 minutes / +30 minutes) intravenous (IV) infusion on Day 1 of each cycle (21 days). intervention 2: Phase I: Dose escalation will follow the classical 3+3 trial design by Fibonacci sequence. Phase II: Maximum tolerated dose (MTD) identified in phase I. Rucaparib will be given orally at designated dose twice a day on days 5 to 19 of every 21-day cycle. intervention 3: Participants will be recommended to have 8 mg of ondansetron taken with a small meal or snack to prevent nausea and vomiting approximately 30 minutes prior to each dose of rucaparib.

Protocol documents:
ICF_001.pdf: 
IRB NUMBER: 20C0013
IRB APPROVAL DATE: 2/14/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/02/2023
Page 1 of 20
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Anish Thomas, M.D.
STUDY TITLE: 
Phase I/II trial of PLX038 (PEGylated SN38) and Rucaparib 
in Solid tumors and Small Cell Cancers.
STUDY SITE: 
NIH Clinical Center
Cohort: 
Affected patient 
Consent Version: 
02/02/2023
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Anish Thomas, MD, by phone at 240-760-7343 or email anish.thomas@nih.gov
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study. 
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you make 
a decision can be found in other sections of the document. Taking part in research at the NIH is 
your choice.
You are being asked to take part in this study because you have small cell lung cancer or small 
cell cancer outside your lungs. You may also be asked to participate in the first part of the study 
only (see description below), if you have a solid tumor.
The purpose of this study is to find safe combination of PLX038 and rucaparib and see if this 
combination will cause your tumors to shrink. 
The use of PLX038 in this study is considered investigational which means it has not been 
approved by the U.S. Food and Drug Administration (FDA) to treat cancer. However, the FDA 
has given us permission to use PLX038 in this study. PLX038 works by blocking a protein, 
called topoisomerase I. Cells need this protein to divide and grow. PLX038 blocks this protein 
so the cancer cells can't divide and grow. 
Rucaparib has been approved by the U.S. Food and Drug Administration (FDA) for use in some 
cancers found primarily in women; however, it is not approved for small cell cancers. Rucaparib 
belongs to group of drugs called PARP inhibitors that target and block several pathways needed 
for cancer cells to grow and cause cancer cell to die.
There are other standard of care drugs and/or procedures that may be used to treat your disease, 
and these can be given to you by your regular cancer doctor if you are not in this study. For 
example: there is chemotherapy and radiation therapy. You may also participate in another 
clinical trial either at the Clinical Center (CC) or another institution. The treatment given in this 
study and the known possible side effects may or may not be significantly different than if you 
were to receive standard care or being in another clinical trial. For example: chemotherapy and 


IRB NUMBER: 20C0013
IRB APPROVAL DATE: 2/14/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/02/2023
Page 2 of 20
CC ICF template v. 09.27.19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
radiation therapy cause fatigue, hair loss, bruising and bleeding, infection, low blood cell counts. 
Immune checkpoint inhibitors may cause inflammation of the lung, intestines or liver, and 
kidney, heart, or problems of the nervous system. Any of these treatments can cause nausea, 
vomiting, diarrhea and rash.
PLX038 and rucaparib have similar side effects to those listed above: low blood cell counts, 
fatigue, nausea, vomiting, diarrhea, rash, changes in kidney and liver function blood tests.
If you become pregnant, there may be unknown risks to the fetus or unborn child, or risks that 
we did not anticipate. There may be long-term effects of the treatment being studied that could 
increase the risk of harm to a fetus. If you are capable of becoming pregnant, you will need to 
use appropriate contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry, for the duration of study treatment and up to 6 months after the last dose of the study 
drug (s). You must tell the study doctor if your birth control method fails while you are in the 
study. If you think or know you have become pregnant during the restricted period, please 
contact the research team member as soon as possible.
If you decide to join this study, here are some of the most important things that you should know 
that will happen:

First, we will perform tests to find out if you fit the study requirements. We will do 
standard blood tests and scans to test your health and see the status of your disease.

In the first part of the study, called phase I, we want to find out what combination of 
PLX038 and rucaparib is safe to use. This safe combination will be used in the second 
part of the study (phase II) to determine if PLX038 and rucaparib will cause tumors to 
shrink. You cannot choose which part of the study to enroll in; enrollment will occur in 
sequential fashion, meaning that participants will enroll as they are screened and 
determined to be eligible.

If you fit the study requirements and decide to take part, you will start your treatment 
with PLX038 and rucaparib. We will then send you home with a supply of rucaparib that 
you will need to take. We will need to see you at the Clinical Center every 3 weeks while 
you are receiving treatment. You will not generally need to stay in the hospital for this 
study. The only exception is possible admission for collection of blood every few hours 
at the beginning of treatment – on days 1, 4 and 6. Each visit should last no more than 8 
hours.

As described above and later in more detail in this consent form, you may have side 
effects if you take part in this study. Some can be mild or very serious, temporary, long-
lasting, or permanent, and may include death. You will be seen regularly during the 
study. You will have clinical, laboratory, and imaging tests to see how you are doing and 
see how your disease is responding. We will also collect required samples from you 
(such as: blood, tumor tissues and hair) for both clinical and research purposes.

After the study treatment has ended we would like to see you in the Clinical Center 
approximately one month later to check on your health. After that we are planning to 
contact you by phone or e-mail to learn about your health status, and to see how you are 
doing, for the rest of your life or until the study is stopped. If you stop treatment for 


IRB NUMBER: 20C0013
IRB APPROVAL DATE: 2/14/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/02/2023
Page 3 of 20
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
reasons other than worsening of your disease, we will continue to invite you for imaging 
studies approximately every 9 weeks until worsening of your disease. You can have 
these studies at home institution and send us the results.
This study may benefit you by shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer. Even if you do not benefit from this study, the results from 
our research will help others in the future.
You are free to stop taking part in the trial at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests to make sure it is safe for you to stop.
The remaining document will now describe more about the research study. This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information described in this document. Some people have personal, religious, or ethical 
beliefs that may limit the kinds of medical or research treatments they would want to receive (such 
as blood transfusions). Take the time needed to ask any questions and discuss this study with NIH 
staff, and with your family, friends, and personal health care providers. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research. 
WHY IS THIS STUDY BEING DONE?
This is a research study. The purpose of this study is to find safe combination of PLX038 and 
rucaparib and see if this combination will cause your tumors to shrink.
We are asking you to join this research study because you have:

A solid tumor (Phase I only) 
OR

Small cell lung cancer or small cell cancer outside your lungs (Phase I or Phase II).
PLX038 is considered investigational which means it has not been approved by the U.S. Food and 
Drug Administration (FDA) to treat your cancer. PLX038 is designed to block a protein, called 
topoisomerase I. Cells need this protein to divide and grow. PLX038 blocks this protein so the 
cancer cells can't divide and grow. 
Rucaparib has been approved by the U.S. Food and Drug Administration (FDA) for use in some 
cancers found primarily in women; however, it is not approved for small cell cancers. Rucaparib 
belongs to group of drugs called PARP inhibitors that target and block several pathways needed 
for cancer cells to grow and cause cancer cell to die. 
WHAT WILL HAPPEN DURING THE STUDY?
For both phase I and Phase II, PLX038 will be administered to you by IV (through an intravenous 
catheter, a small plastic tube that is put into a vein, usually in your arm) on Day 1 of each cycle (1 
Cycle = 21 days).


IRB NUMBER: 20C0013
IRB APPROVAL DATE: 2/14/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/02/2023
Page 4 of 20
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
You will take rucaparib by mouth on Day 6 of Cycle 1 and continue for 14 days with the last doses 
on Day 19 followed by seven days without rucaparib treatment. You will continue this schedule 
of rucaparib dosing on days 6-19 of every 21 days cycle. If we have to shorten or lengthen the 
cycle for any reason, we will instruct you further on when to stop taking rucaparib. 
Rucaparib should be taken 2 times a day. Try to space your doses out evenly throughout the day, 
so ideally, take a dose at 8 am and 8 pm. You may take the tablets with or without food. If you 
need to take your rucaparib earlier than scheduled or you missed a dose, you can take it in the time 
period of +/- 2 hours of the scheduled time. If you vomit after taking rucaparib, please, do not 
immediately take another tablet. You should simply proceed with next dose as scheduled.
If you have nausea or vomiting caused by rucaparib, we will give you ondansetron to prevent it. 
You will need to take ondansetron by mouth with small meal or snack approximately 30 minutes 
prior to each dose of rucaparib.
During each cycle, you will be given growth colony stimulating factor (G-CSF) at least 72 hours 
after PLX038 administration. G-CSF is a medication that stimulates the production of blood cells. 
This will help prevent and/or treat low white blood cells which is usually a risk associated with 
cancer treatment.
You will be given a Medication Diary to complete for each cycle. In the diary, you will be asked 
to record the date and time of each dose of rucaparib. You will also be asked to record missed 
doses. Please bring the diary with you at every study visit.
At each visit, please also bring empty bottles and any unused medication you may have.
Rucaparib may increase your sensitivity to sunlight. You should take all of the usual sun protection 
precautions when going outside. It is advised that you avoid excessive sun exposure, wear 
protective clothing (including wearing a hat and sunglasses), and use sunscreens regularly (sun 
protection factor 50 or greater).
If your doctor is convinced that you have unacceptable side effects caused by one of treatment 
drugs, this drug will be stopped, and you may continue treatment with the other drug if your study 
doctor finds that it is in your interest. Treatment will continue until you have unacceptable side 
effects (both drugs) or you are no longer benefiting from the study therapy.
Treatment and all study related procedures will be done during outpatient visits without planned 
hospitalization. However, we might still choose to keep your overnight if needed for blood 
collection and other situations that arise.
Before you begin the study
Before you begin this study, you will need to have standard clinical exams and tests to make sure 
you are eligible for this study. The exams and tests are part of regular cancer care. Most of these 
tests will be done under a separate protocol. 
You will be asked to provide documentation to confirm your diagnosis. If documentation is not 
available, we will perform a biopsy (collect a sample of your tumor) to confirm your diagnosis.
We may also perform an additional blood test telling us about the status of a certain gene that 
affects how safe the study therapy might be for you. We may also perform an electrocardiogram 
(EKG – a record of your heartbeat) to evaluate your heart.


IRB NUMBER: 20C0013
IRB APPROVAL DATE: 2/14/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/02/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If treatment does not start within 28 days after enrollment to this study, some tests may need to be 
repeated.
During the study 
Ongoing procedures before treatment and with every cycle: 

Physical examination, including weight and vital signs.

Review of your symptoms, medications and your ability to perform your normal activities.

Discussion of any symptoms you might be having

Routine blood tests to find out if you are anemic, have low blood counts, and if your liver, 
kidneys, thyroid, clotting system and other organs are working well. About a tablespoon 
and a half may be collected at each timepoint.

Pregnancy test if you are a woman who can have children.
Ongoing procedures before treatment and every 3 cycles:

Imaging assessments/scans – either a CT (a series of x-ray images taken of parts of your 
body) or MRI (magnetic testing, which does not involve any radiation) of chest, abdomen 
and pelvis. 
A computer tomography (CT) scan produces a series of x ray images taken of parts of your body.
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to take pictures 
of your body. The MRI scanner is a metal cylinder surrounded by a strong magnetic field. During 
the MRI, you will lie on a table that can slide in and out of the cylinder. We will place soft padding 
or a coil around your head. You will be in the scanner about 30 minutes. You may be asked to lie 
still for up to 30 minutes at a time. While in the scanner you will hear loud knocking noises, and 
you will be fitted with earplugs or earmuffs to muffle the sound. You will be able to communicate 
with the MRI staff at all times during your scan, and you may ask to be moved out of the machine 
at any time.
Additional research testing
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you for purposes of 
research only. The samples are being done to look at the effects of therapy on your immune system 
and markers of tumor activity, including collecting and testing tumor cells. 
The samples included for these studies include:

Blood samples to study:
drugs levels in your blood on day 1, day 6 and day 8 (optional) of cycle 1 and on day 1 
of cycles 2-4 (up to a little more than 1 tablespoon at each timepoint).

Blood and hair to study:
how well your tumor responds to treatment on day 1, 6 and 7 of cycle 1 and on day 1 
of cycle 2 (hair samples). 


IRB NUMBER: 20C0013
IRB APPROVAL DATE: 2/14/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/02/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
how your body responds to treatment on day 1, day 6, day 7 of cycle 1, on day 1 of 
cycle 2 and when your disease progresses (blood sample – up to 3 and a half 
tablespoons at each timepoint). Blood for certain tests may not be collected if no hair 
sample was obtained.

Tumor biopsy:
We will ask you to provide samples of your tumors from previous surgeries or biopsies 
if available. We also may perform three optional tumor biopsies before treatment, on 
day 4 or 6 and between days 7 and 14 of cycle 1. Please see Risks from Biopsy section 
for the risks of biopsy. You will be asked to sign a separate consent each time you agree 
to have an optional biopsy. You can participate in the study even if you decide not to 
undergo the biopsy procedures. Samples will be used to study how well your tumor 
responds to treatment, all of your tumor genes and how well they are working. 
I agree to participate in the additional research testing described above.
_____ Yes
_____ No
Initials
Initials 
Tumor samples collected for research purposes on this study may be used to look for specific 
changes in the DNA in tumors that could be used to develop new ways of diagnosing and treating 
cancer. DNA (also called deoxyribonucleic acid) in the cells carries genetic information and passes 
it from one generation of cells to the next – like an instruction manual. Normal tissue contains the 
DNA (instructions) that you were born with, DNA in tumor cells has changed – or mutated – and 
we think that change in the DNA is what causes tumors to form and to grow. RNA (also called 
ribonucleic acid) carries the instructions from the DNA to the parts of your cells that make proteins. 
To look at your DNA and RNA, we may do what is called “DNA or RNA sequencing.” This is 
where we will do special tests in the lab to look at the sequence, or order, of how your DNA or 
RNA are put together. This is what makes you unique. 
To determine which parts of the DNA or RNA have mutated, we will compare the DNA or RNA 
in your tumor cells to DNA or RNA from normal cells. We will then analyze the results from 
similar tumors to see if there are any changes in the DNA or RNA that are common to a particular 
type of tumor.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For these reasons, we will 
not give you the results of the research tests done on your research samples in most cases. There 
may be exceptions to what we share with you and this is described later in this consent form in the 
section for “Return of research results”.
When you are finished taking the drugs (treatment)
Approximately 30 days after you have finished taking the study drug, you will be asked to return 
to Clinical Center for a safety follow up visit. At this visit, you will be asked questions about your 
health, get a physical exam and undergo blood tests. 


IRB NUMBER: 20C0013
IRB APPROVAL DATE: 2/14/2023
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 02/02/2023
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If you have been taken off treatment for reasons other than worsening of your disease, you will 
continue to have imaging studies approximately every 9 weeks until worsening of your disease. 
You can have these studies at home institution and send us results.
If you are unable to return for these visits, we will obtain the information from you by telephone 
or e-mail.
Once you stop coming to Clinical Center for safety visits and your scans, we will call or e-mail 
you every 6 months to ask you about your general well-being.
HOW LONG WILL THE STUDY TAKE?
You will come for study treatments every 21 days until your disease gets worse or you have 
unacceptable side effects at which time we will stop treatment.
Visits will range from 4-8 hours in length.
After stopping treatment, we would like to see you in the NIH Clinical Center one month later and 
follow you after that for the rest of your life by telephone or e-mail. 
If you stop treatment for reasons other than worsening of your disease, we would like to invite you 
for imaging studies approximately every 9 weeks until worsening of your disease. 
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have up to 65 people take part in this study.
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
The drug used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last longer.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect.

The study doctor may be able to treat some side effects.

The study doctor may adjust the study drugs to try to reduce side effects.


IRB NUMBER: 20C0013
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Risks of Rucaparib
VERY COMMON 
In 100 people receiving rucaparib, more than 10 may have:

Nausea 

Feeling tired 

Low blood counts (red blood cells, white blood cells, and platelets). Sometimes fever 
occurs with the low blood counts. These low blood count effects may be more likely to 
occur after multiple cycles of treatment.
o
A low red blood cell count may make you feel tired or dizzy. If you feel dizzy 
while taking rucaparib, you should avoid potentially hazardous tasks such as 
driving or operating machinery.
o
A low white blood cell count puts you at higher risk for bacterial or viral 
infections. Having a high temperature or fever while your white blood cell count 
is low is a life threatening medical emergency and you must proceed to the 
nearest emergency room as soon as possible. 
o
A low platelet count affects the ability of your blood to clot and could lead to 
bleeding events. Symptoms include but are not limited to easy bruising, 
prolonged bleeding from cuts, blood in stools or urine, or nose bleeding.

A low phosphate level in your blood. Usually there are no symptoms but if the levels 
are critically low, you may notice trouble breathing, confusion, muscle weakness, 
and/or irritability.

Increase in cholesterol. If your cholesterol increases significantly, your doctor may 
prescribe a medicine to lower your cholesterol level.

Changes in kidney and liver function blood tests that may indicate a sudden decrease in 
your kidney or liver function. Changes in liver function blood tests can also indicate 
liver injury caused by various medications. These blood test changes will be evaluated 
by your study doctor along with any other side effects that you are experiencing as well 
as other test results.

Changes in your sense of taste.

Stomach-related effects such as constipation, vomiting, diarrhea, decreased appetite, 
stomach pain (epigastric pain), and indigestion. 

Difficulty breathing possibly from an inflammation of the lungs that may or may not be 
caused by a bacterial or viral infection. 

Dizziness

Sensitivity to sunlight. 

Fever sometimes can occur independent of a low blood count.


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VERY COMMON 
In 100 people receiving rucaparib, more than 10 may have:

Difficulty sleeping 

Constipation

Fatigue or weakness
FREQUENT
In 100 people receiving rucaparib, more than 1 and less than 10 may have:

Rash. Some rashes may be itchy, painful, or cause no symptoms at all. 

Itchy skin 

Infection. Low white blood cells may put you at risk for an infection that may lead to 
sepsis (chain reaction throughout your body which injures or damages tissues and 
organs) or shock (a sudden drop in blood pressure with loss of consciousness and/or 
possible seizures, including the possibility of death).

Redness, swelling, and pain on the palms of the hands and/or the soles of the feet. 
Sometimes blisters appear.

When a small amount of drug leaks out of the blood vessels, it damages the surrounding 
tissues. Symptoms may include tingling, burning, redness, flaking, swelling, blistering, 
and sores of the hands and feet due to the increased friction and heat your extremities 
are exposed to. If you experience these symptoms, apply ice packs and elevate hands 
and feet, then contact your study doctor immediately for treatment

Stomach cramps, loss of appetite, constipation, vomiting, inability to have a bowel 
movement or pass gas, swelling of the abdomen caused by a blockage in the intestines.

Blood in the urine.

Inflammation or sores along the inner surface of the mouth

You could have allergic reactions to the study drug, such as itching, skin rash, facial 
swelling, and/or a severe or sudden drop in blood pressure. A sudden drop in blood 
pressure could lead to shock with loss of consciousness and/or possible seizures, 
including the possibility of death. If you have any of the above symptoms, seek medical 
attention right away.
LESS FREQUENT
In 100 people receiving rucaparib, up to 1 may have:

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been 
reported in participants treated with rucaparib. MDS is a pre-cancerous condition where 


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LESS FREQUENT
In 100 people receiving rucaparib, up to 1 may have:
the bone marrow is not as good at producing blood cells (red and/or white blood cells 
and/or platelets). People with MDS need transfusions (red blood cells and/or platelets) 
and/or other treatments. In some cases, MDS can progress to AML, which is a cancer of 
the bone marrow where more abnormal and immature white blood cells (also called 
blasts) are made than normal white blood cells. People with AML need treatment with 
chemotherapy and/or a bone marrow transplant. Participants may develop AML without 
first being diagnosed with MDS.
. 
Based on other research studies and animal studies, the following are potential risks that we will 
monitor:

Embryofetal toxicity (risks to your unborn baby)

An irregular heart rhythm that can be seen on an electrocardiogram related to a disturbance 
in how the heart's bottom chambers (ventricles) send signals 

Development of a new cancer
Risks from PLX038
COMMON

Low white blood cells which can increase the risk of infection that may lead to sepsis 
(chain reaction throughout your body which injures or damages tissues and organs) or 
shock (a sudden drop in blood pressure with loss of consciousness, including the 
possibility of death). Having a high temperature or fever while your white blood cell count 
is low is a life threatening medical emergency and you must proceed to the nearest 
emergency room as soon as possible.

Low red blood cell count which can give you shortness of breath, weakness fatigue

A low platelet count which can cause easy bruising or bleeding

Diarrhea

Abdominal Pain

Inflammation (swelling and redness) of the large bowel (colon)

Decreased blood level of potassium 

Dehydration 
POTENTIAL SIDE EFFECTS BASED ON ANIMAL STUDIES:

Diarrhea


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
Nausea

Vomiting

Decreased appetite

Hair loss

Dark spots of the cornea, the transparent front part of the eye, which may cause loss of 
vision. Small spots appeared in the eyes of some monkeys that were administered PLX038. 
After stopping the drug, the spots may or may not go away

Liver damage
RARE, AND SERIOUS

Allergic reaction to the drug or one of the ingredients in the drug. An allergic reaction may 
include a rash, wheezing, shortness of breath, heart palpitations, swelling of the face and 
lowered blood pressure. Rarely, allergic reactions can be life threatening or can cause 
death.
Getting medical treatment right away may keep these problems from becoming more serious. Let 
your study doctor know of any questions you have about possible side effects. You can ask the 
study doctor questions about side effects at any time.
Risks from Biopsy 
This procedure usually causes only brief discomfort at the site from which the biopsy is taken. 
Risks of biopsy may include bleeding, injury to internal organs, and infection. Rarely, these 
complications from biopsy could result in hospitalization and require additional medical care. 
Risks of sedation will be described at the time of procedure. 
Risks from Blood Collection 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood 
cell count (anemia) can develop.
Risks associated with Hair Collection
You may feel some light pain and discomfort from hair collection.
What are the risks related to pregnancy? 
If you are capable of becoming pregnant, we will ask you to have a pregnancy test before beginning 
this study. For a portion of the study, you will need to use effective birth control methods and try 
not to become pregnant. Your study team will provide additional details on how long this will be 
required and what methods may be used. If you become pregnant, there may be unknown risks to 
the fetus or unborn child, or risks that we did not anticipate. There may be long-term effects of the 
treatment being studied that could increase the risk of harm to a fetus. You must tell the study 
doctor if your birth control method fails while you are in the study. If you think or know you have 


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become pregnant during the restricted period, please contact the research team member identified 
at the top of this document as soon as possible. If you plan to become pregnant in the future, you 
must agree to use appropriate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study treatment and for 6 months after 
treatment.
You may not participate in this study if you are pregnant. If you are capable of becoming pregnant, 
we will perform a pregnancy test before exposing you to radiation. You must tell us if you may 
have become pregnant within the previous 14 days because the pregnancy test is unreliable during 
that time.
If you are a sexually active person with a partner capable of becoming pregnant, it is important 
that your partner not become pregnant for the time period discussed with your study team. There 
may be unknown risks to a fetus or risks we did not anticipate. You and your partner must agree 
to use birth control if you want to take part in this study. If you think your partner has become 
pregnant during the restricted time period, please contact the research team member identified at 
the top of this document as soon as possible. If you and your partner plan for your partner to 
become pregnant after the restricted time period, please discuss this with the study team.
What are the risks of radiation from being in the study? 
During your participation in this research study, you may be exposed to radiation from up to 5 CTs 
and 3 CT guided biopsies each year. The amount of radiation exposure from these procedures is 
equal to approximately 7.9 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them. The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources. This type of radiation is called “background radiation.” 
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans that you get in this study will expose you to the roughly the same amount of radiation 
as 26.3 years’ worth of background radiation. Being exposed to too much radiation can cause 
harmful side effects such as an increase in the risk of cancer. The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from 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%). 
Risks from CT scans
If contrast dye is used, there is a risk for allergic reaction to the dye. If you are allergic to or 
sensitive to medications, contrast dye, iodine, or shellfish, please notify your study doctor. If you 
have had kidney failure or other kidney problems in the past, please notify your study doctor.
Privacy Risks Associated with Genetic Testing
It may be possible that genetic information from you could be used by law enforcement agencies 
or other entities to identify you or your blood relatives.


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Psychological or Social Risks Associated with Return of Incidental or Secondary Findings 
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them.  
Protections against misuse of genetic information 
This study involves genetic testing on samples. Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
However, the potential benefit to you might include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because what we learn in this study may 
eventually be used to treat others with your disease. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether to be in this study, we will discuss the other options that are available 
to you. Instead of being in this study, you could:

choose to be treated with surgery, radiation or with drugs already approved by the FDA for 
your disease

choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
You should discuss with your doctor your other choices and their risks and benefits.


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DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research. These are known as “incidental medical 
findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid. Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab. However, in the unlikely 
event that we discover a finding believed to be clinically important based on medical standards at 
the time we first analyze your results, we will contact you. This could be many years in the future. 
We will ask you to provide another sample to verify the findings we have seen in our lab. If the 
results are verified, you will be re-contacted and offered a referral to a genetic Healthcare Provider 
To Discuss The Results.
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if your disease worsens or comes back during treatment

if you become pregnant

if you have side effects from the treatment that your doctor thinks are too severe

if the PLX038 and rucaparib become unavailable

if new information shows that another treatment would be better for you

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped.
After the therapy is stopped, we would like to see you for a safety visit approximately one month 
after stopping therapy.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.


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If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will Your Specimens or Data Be Saved for Use in Other Research Studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding cancer, or other diseases or 
conditions. This could include studies to develop other research tests, treatments, drugs, or 
devices, that may lead to development of a commercial product by the NIH and/or its research 
or commercial partners. There are no plans to provide financial compensation to you if this 
happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you.
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials 
We may share your coded specimens and data with other researchers. If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you. They may be doing research in areas similar to this research or in other unrelated areas. 
These researchers may be at NIH, other research centers and institutions, or commercial entities. 
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 


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In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places. When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you. We will not contact you to 
ask your permission or otherwise inform you before we do this. We might do this even if you 
answered "no" to the above questions. If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical record 
number; and your data will be labeled with only a code. We cannot offer you a choice of whether 
your data to be placed in this database or not. If you do not wish to have your data placed in this 
database, you should not enroll in this study. 
Will Your Genomic Data Be Shared Outside of This Study?
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex. If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we 
cannot offer you a choice of whether your data will be shared. If you do not wish to have your 
data placed in a repository, you should not enroll in this study. 
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely.
Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.


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COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. Someone will work 
with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST (COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a COI Guide. You may ask your research team for a copy of 
the COI Guide or for more information. Members of the research team who do not work for NIH 
are expected to follow these guidelines or the guidelines of their home institution, but they do not 
need to report their personal finances to the NIH.
The NIH and the research team for this study are using PLX038 developed by ProLynx LLC 
through a joint study with your study team and the company. The company also provides financial 
support for this study. 
Clovis Oncology, Inc. is providing rucaparib for this study to NIH without charge. No NIH 
investigator involved in this study receives payments or other benefits from any company whose 
drug, product or device is being tested. However, there are some research partners not associated 
with the NIH working on this study who may receive payments or benefits, limited by the rules of 
their workplace


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CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY 
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor Center for Cancer Research of National Cancer Institute.

Qualified representatives from ProLynx LLC and Clovis Oncology, Inc., the 
pharmaceutical companies who produce PLX038 and rucaparib.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.. However, if you sign a release of information form, for example, for an 
insurance company, the NIH will give the insurance company information from your medical 
record. This information might affect (either favorably or unfavorably) the willingness of the 
insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances. 
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court. 
The Certificate does not protect your information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
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Prot_SAP_002.pdf: 
Abbreviated Title: PLX038 and Rucaparib
Version Date: 03/11/2024
1
Abbreviated Title: PLX038 and Rucaparib 
NIH Protocol: 20-C-0013 
Version Date: 03/11/2024
NCT Number: NCT04209595
Title: Phase I/II trial of PLX038 (PEGylated SN38) and Rucaparib in Solid tumors and Small 
Cell Cancers 
NCI Principal Investigator:  
   Anish Thomas, MD 
Developmental Therapeutics Branch (DTB)
National Cancer Institute (NCI)
10 Center Drive, Room 4-5330
Bethesda, MD 20892
Phone: 240-760-7343
E-mail: anish.thomas@nih.gov 
Drug Name:
PLX038 (PEGylated SN38)
Rucaparib
IND Number:
145310
145310
Sponsor:
CCR, NCI
CCR, NCI
Manufacturer:
ProLynx LLC
Clovis Oncology, Inc.
Supplier:
ProLynx LLC
Clovis Oncology, Inc.
Safety Monitoring Committee (SMC): NCI SMC


Abbreviated Title: PLX038 and Rucaparib
Version Date: 03/11/2024
2
PRÉCIS 
Background:

We hypothesize that a dose-escalation strategy that incorporates tumor targeted DNA-
damaging chemotherapy and DNA-damage response (DDR) inhibitors could allow safe 
and effective administration of DDR inhibitor-chemotherapy combination. 

PLX038 is a PEGylated conjugate of SN38 with improved properties including increased 
solubility, higher exposure and longer half-life. SN-38 is the active metabolite of CPT-11 
(irinotecan) that inhibits topoisomerase 1 (Top1) and causes DNA strand breakage. As a 
specific DNA damaging agent, SN-38 enhances cell kill in tumors deficient in the DNA-
damage response and when combined with inhibitors of the DDR.

Rucaparib is a potent oral poly ADP ribose polymerase (PARP) inhibitor that is approved 
for the maintenance treatment of participants with recurrent epithelial ovarian, fallopian 
tube, or primary peritoneal cancer who are in a complete or partial response to platinum-
based chemotherapy.

We hypothesize that the combination of PLX038 plus rucaparib is more efficacious than 
either agent alone.
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 participants with small cell lung cancer and extra-pulmonary 
small cell carcinomas. 
Eligibility:

Subjects with histologically confirmed solid tumors (Phase I) OR histologically or 
cytologically confirmed small cell lung cancer (SCLC) (Phase II) OR histologically or 
cytologically confirmed extra-pulmonary small cell carcinomas (Phase II).

Age ≥18 years

Subjects must have evaluable or measurable disease.

ECOG performance status ≤ 2

Adequate organ function
Design:

This is an open label Phase I/II trial accruing initially one cohort to determine maximum 
tolerated dose (MTD) of combined treatment of PLX038 and rucaparib (Phase I); and to 
examine the safety and efficacy of PLX038 in combination with rucaparib in the following 
cohort (Phase II). 

PLX038 will be administered by IV infusion on day 1 of every 21-days cycle, rucaparib 
will be administered PO twice daily on days 6 to 19 of every cycle.


Abbreviated Title: PLX038 and Rucaparib
Version Date: 03/11/2024
3

Treatment will continue until progression or unacceptable toxicity.

Biomarkers of participant response to treatment will be investigated in an exploratory 
manner pre and post-treatment.


Abbreviated Title: PLX038 and Rucaparib
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4
TABLE OF CONTENTS
PRÉCIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................4
STATEMENT OF COMPLIANCE ..............................................................................................10
1
INTRODUCTION .................................................................................................................11
1.1
Study Objectives .............................................................................................................11
1.1.1
Primary Objectives ..................................................................................................11
1.1.2
Secondary Objectives ..............................................................................................11
1.1.3
Exploratory Objectives ............................................................................................11
1.2
Background and Rationale..............................................................................................11
1.2.1
Small cell lung cancer (SCLC) and extrapulmonary small cell carcinoma.............12
1.2.2
SN-38 and PLX038..................................................................................................14
1.2.3
Rucaparib.................................................................................................................22
1.2.4
Rationale for this study............................................................................................29
1.2.5
Rationale for Amendment to Change Dose-Escalation Strategy (Amendment 
Version Date: 03/19/2021) ....................................................................................................30
1.2.6
Additional Summary Safety and Efficacy Results and Rationale for Further 
Changes to Dose Escalation Strategy (as of amendment version date: 04/08/2022) ............33
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................38
2.1
Eligibility Criteria ...........................................................................................................38
2.1.1
Inclusion Criteria .....................................................................................................38
2.1.2
Exclusion Criteria ....................................................................................................39
2.1.3
Recruitment Strategies.............................................................................................40
2.2
Screening Evaluation ......................................................................................................40
2.2.1
Screening activities performed prior to obtaining informed consent ......................40
2.2.2
Screening activities performed after a consent for screening has been signed........40
2.3
Participant Registration and Status Update Procedures..................................................41
2.3.1
Treatment Assignment Procedures..........................................................................41
2.4
Baseline Evaluation.........................................................................................................42
3
STUDY IMPLEMENTATION .............................................................................................42
3.1
Study Design...................................................................................................................42


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5
3.1.1
Dose Limiting Toxicity............................................................................................43
3.1.2
Phase I Cohort..........................................................................................................43
3.1.3
Phase II Cohorts.......................................................................................................44
3.2
Study Stopping Rules......................................................................................................45
3.3
Drug Administration .......................................................................................................45
3.3.1
PLX038....................................................................................................................45
3.3.2
Rucaparib.................................................................................................................45
3.4
Dose Delay or Modifications ..........................................................................................45
3.4.1
Phase I during evaluation period .............................................................................45
3.4.2
Phase I after DLT evaluation period and Phase II...................................................46
3.5
Study Calendar................................................................................................................48
3.6
Cost and Compensation ..................................................................................................52
3.6.1
Costs ........................................................................................................................52
3.6.2
Compensation ..........................................................................................................52
3.6.3
Reimbursement........................................................................................................52
3.7
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................52
3.7.1
Criteria for Removal from Protocol Therapy ..........................................................52
3.7.2
Off -Study Criteria...................................................................................................52
3.7.3
Lost to Follow-up ....................................................................................................52
4
CONCOMITANT MEDICATIONS/MEASURES...............................................................53
4.1
Prohibited Medications ...................................................................................................53
4.1.1
Strong inducers or inhibitors of CYP3A4 and UGT1A1 inhibitors ........................53
4.2
Required Medication.......................................................................................................53
4.2.1
G-CSF......................................................................................................................53
4.3
Recommended Medication .............................................................................................53
5
CORRELATIVES STUDIES FOR RESERACH .................................................................53
5.1
Biospecimen Collection ..................................................................................................53
5.2
Collection of Samples .....................................................................................................57
5.2.1
Blood........................................................................................................................57
5.2.2
Tumor samples.........................................................................................................57
5.2.3
Hair follicles ............................................................................................................57


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5.3
Correlative Studies for Research.....................................................................................57
5.3.1
Pharmacokinetic analysis.........................................................................................57
5.3.2
The formation of γH2AX foci .................................................................................57
5.3.3
PARP inhibition.......................................................................................................57
5.3.4
SLFN11....................................................................................................................58
5.3.5
Immune Subset Analysis .........................................................................................58
5.3.6
Circulating Tumor DNA..........................................................................................59
5.3.7
Interference of PLX038 with coagulation assays ....................................................59
5.3.8
SLFN11 Expression.................................................................................................60
5.3.9
RNAseq and Whole Exome Sequencing .................................................................60
5.3.10
Management of Results ...........................................................................................60
5.3.11
Genetic Counseling..................................................................................................60
5.4
Sample Storage, Tracking And Disposition....................................................................61
5.4.1
Samples Managed by Dr. Figg’s Blood Processing Core (BPC) ............................61
5.4.2
Procedures for storage of participant samples in the DTB Clinical Translational 
Unit
62
5.4.3
Procedures for storage of participant samples in the Laboratory of Dr. Redon ......62
5.4.4
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology ........63
5.4.5
Procedures for storage of tissue and blood samples in the Laboratory of Dr. Kumar
63
5.4.6
Procedures for Storage of PLX038 Coagulation Assay Blood Samples in the 
Department of Laboratory Medicine (DLM).........................................................................64
5.4.7
Protocol Completion/Sample Destruction ...............................................................64
6
DATA COLLECTION AND EVALUATION .....................................................................64
6.1
Data Collection ...............................................................................................................64
6.2
Data Sharing Plans..........................................................................................................65
6.2.1
Human Data Sharing Plan .......................................................................................65
6.2.2
Genomic Data Sharing Plan.....................................................................................65
6.3
Response Criteria ............................................................................................................65
6.3.1
Disease Parameters ..................................................................................................66
6.3.2
Methods for Evaluation of Measurable Disease......................................................67
6.3.3
Response Criteria.....................................................................................................68


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6.4
Toxicity Criteria..............................................................................................................70
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...70
7.1
Definitions.......................................................................................................................70
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................70
7.2.1
Expedited Reporting ................................................................................................70
7.2.2
IRB Requirements for PI Reporting at Continuing Review ....................................71
7.3
NCI Clinical Director Reporting.....................................................................................71
7.4
NIH Required Data and Safety Monitoring Plan............................................................71
7.4.1
Principal Investigator/Research Team.....................................................................71
7.4.2
Safety Monitoring Committee (SMC).....................................................................71
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................72
8.1
Definitions.......................................................................................................................72
8.1.1
Adverse Event..........................................................................................................72
8.1.2
Serious Adverse Event (SAE) .................................................................................72
8.1.3
Life-threatening .......................................................................................................72
8.1.4
Severity....................................................................................................................72
8.1.5
Relationship to Study Product .................................................................................73
8.1.6
Adverse Events of Special Interest (AESI) .............................................................73
8.2
Assessment of Safety Events ..........................................................................................73
8.3
Reporting of Serious Adverse Events .............................................................................74
8.4
Waiver of Expedited Reporting to CCR .........................................................................74
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators......................................74
8.6
Reporting Pregnancy.......................................................................................................74
8.6.1
Maternal exposure ..................................................................................................75
8.6.2
Paternal exposure.....................................................................................................75
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND...................75
8.8
Sponsor Protocol Deviation Reporting ...........................................................................75
9
CLINICAL MONITORING..................................................................................................76
10
STATISTICAL CONSIDERATIONS ..................................................................................76
10.1
Study Objective ...........................................................................................................76
10.1.1
Primary Objectives ..................................................................................................76


Abbreviated Title: PLX038 and Rucaparib
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8
10.1.2
Secondary Objectives ..............................................................................................77
10.2
Sample Size Determination.........................................................................................77
10.3
Populations for Analyses.............................................................................................78
10.4
Statistical Analyses......................................................................................................78
10.4.1
General Approach....................................................................................................78
10.4.2
Analysis of the Primary Efficacy Endpoints ...........................................................78
10.4.3
Analysis of the Secondary Efficacy Endpoints .......................................................78
10.4.4
Safety Analyses .......................................................................................................78
10.4.5
Baseline Descriptive Statistics.................................................................................78
10.4.6
Planned Interim Analyses........................................................................................78
10.4.7
Exploratory Analyses...............................................................................................78
11
COLLABORATIVE AGREEMENT ....................................................................................79
11.1
Cooperative Research and Development Agreement (CRADA)................................79
11.2
Clinical Trial Agreement (CTA) .................................................................................79
12
HUMAN SUBJECTS PROTECTIONS................................................................................79
12.1
Rationale for Subject Selection ...................................................................................79
12.2
Participation of Children .............................................................................................79
12.3
Evaluation of Benefits and Risks/Discomforts ...........................................................79
12.3.1
Benefits....................................................................................................................79
12.3.2
Risks ........................................................................................................................80
12.3.3
Assessment of Potential Risks and Benefits............................................................83
12.4
Consent Process and Documentation ..........................................................................83
13
REGULATORY AND OPERATIONAL CONSIDERATIONS..........................................84
13.1
Study Discontinuation and Closure.............................................................................84
13.2
Quality Assurance and Quality Control ......................................................................85
13.3
Conflict of Interest Policy ...........................................................................................85
13.4
Confidentiality and Privacy.........................................................................................85
14
PHARMACEUTICAL INFORMATION .............................................................................86
14.1
PLX038 (IND 145310)................................................................................................86
14.1.1
Source ......................................................................................................................86
14.1.2
Acquisition and Accountability ...............................................................................86


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9
14.1.3
Formulation and Preparation ...................................................................................86
14.1.4
Stability and Storage................................................................................................87
14.1.5
Administration Procedures ......................................................................................87
14.1.6
Toxicity....................................................................................................................87
14.2
Rucaparib (IND 145310).............................................................................................87
14.2.1
Source ......................................................................................................................87
14.2.2
Acquisition and Accountability ...............................................................................87
14.2.3
Formulation and Preparation ...................................................................................87
14.2.4
How Supplied ..........................................................................................................87
14.2.5
Administration .........................................................................................................87
14.2.6
Toxicity....................................................................................................................87
15
REFERENCES ......................................................................................................................88
16
APPENDICES .......................................................................................................................92
16.1
Appendix A - Performance Status Criteria..................................................................92
16.2
Appendix B - Patient’s Medication Diary...................................................................93


Abbreviated Title: PLX038 and Rucaparib
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10
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 

United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


Abbreviated Title: PLX038 and Rucaparib
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11
1
INTRODUCTION
1.1
Study Objectives
1.1.1
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 participants with small cell lung cancer. 
1.1.2
Secondary Objectives

To assess safety and tolerability of combined treatment of PLX038 and rucaparib

To determine the progression-free survival (PFS) in Phase II

To determine overall survival (OS) in Phase II

To assess the clinical response rate (CRR) (CR+PR) according to Response Evaluation 
Criteria (RECIST 1.1) in participants with small cell lung cancer.
1.1.3
Exploratory Objectives

To identify pharmacodynamic markers of response including γ H2AX 

To identify predictors of response 

To assess pharmacokinetics of PLX038 and rucaparib

To preliminarily assess the clinical outcomes of participants with extrapulmonary SCLC

To describe and investigate the interference of PLX038 with coagulation assays
1.2
Background and Rationale
PARP inhibitors are now approved for various indications and are under investigation for various 
tumor types. Despite promising preclinical data, chemotherapy-PARP inhibitor combinations have 
proved challenging in clinic. Dose limiting toxicities, specifically myelosuppression, has severely 
limited the ability to dose escalate both PARP inhibitors (PARPi) and chemotherapy in several 
clinical studies [1-7] (Table 1). We hypothesize that a dose-escalation strategy that incorporates 
tumor targeted DNA-damaging chemotherapy and DDR inhibitors could allow higher dose 
administration of DDR inhibitor-chemotherapy combinations. Combinations of PARP inhibitors 
with DNA damaging chemotherapy is likely to be most effective in high replicative (HR) stress 
tumors[8] and in tumors with defects in DNA repair pathways including HR stress tumors such as 
ovarian, breast, and prostate cancers. 


Abbreviated Title: PLX038 and Rucaparib
Version Date: 03/11/2024
12
Table 1. Trials of PARP inhibitors with topoisomerase inhibitors
Combination
MTD
Topo 
1 
inhibitors
% 
of 
MTD
PARP
i
% of 
MTD
DLT
Ref
Irinotecan 200 mg/m2; 
q3w
Olaparib 50 mg qd 
days 1-21
57%
6%
Diarrhea, 
myelosuppression
Irinotecan
Olaparib
Irinotecan 125 mg/m2 
q2w
Olaparib 50 mg bid 
days 1-5
≈69%
≈12%
Anorexia/fatigue
[5]
Irinotecan
Velipari
b
Irinotecan 100 mg/m2 
days 1, 8; subsequent 
q3w
Veliparib 40 bid days 
1-14
≈80
≈10%
Diarrhea, fatigue, 
myelosuppression
[2]
Topoteca
n
Olaparib 
Topotecan 1 mg/m2 on 
days 1-3; subsequent 
q3w
Olaparib 100 mg bid 
days 1-21
≈40%
25%
Myelosuppression
[3]
Topoteca
n
Velipari
b
Topotecan 0.6 mg/m2 
on 
days 
1-5; 
subsequent q3w
Veliparib 10 bid days 
1-5
40%
≈3%
Myelosuppression
[4]
1.2.1
Small cell lung cancer (SCLC) and extrapulmonary small cell carcinoma.
Small cell lung cancer (SCLC) is the most aggressive and lethal form of lung cancer. Because of 
frequent chromosomal alterations, dysregulation of genes that promote replication origin firing 
(e.g., MYC) and the high expression of DNA damage repair proteins, we have postulated that 
SCLC has high levels of endogenous replicative DNA replication forks due to various 
perturbations that interfere with replication [9]. 


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13
SCLC represents 15% of all lung cancers, with an annual incidence of over 34,000 cases in the 
United States alone. SCLC is characterized by rapid doubling time, high growth fraction and early 
and widespread metastatic involvement [10]. Response rates to first-line chemotherapy are 
exceptionally high, on the order of 60% to 70%. Unfortunately, these responses are also 
disappointingly transient, with median PFS of <5 months [11, 12] and nearly all participants 
relapse within one year. Extensive-stage SCLC is generally unresponsive to chemotherapy at 
relapse, and fewer than 5% of participants survive for two years [10]. Treatment of SCLC as well 
as survival after a diagnosis of SCLC have not changed substantially in the past 30 years [13]. 
Due to an urgent need for effective interventions in this disease, SCLC was singled out by the NCI 
as a designated “recalcitrant” cancer based on incidence rate, exceptionally high lethality, and the 
lack of substantial therapeutic progress made over several decades [14]. 
At the time of diagnosis most participants (60-70%) have extensive-stage (ES) disease, defined as 
cancer that has spread beyond the ipsilateral lung and regional lymph nodes and cannot be included 
in a single radiation field [10]. The primary treatment modality for participants with ES-SCLC is 
systemic chemotherapy consisting of platinum and etoposide followed by prophylactic cranial 
irradiation in participants with a response [15]. Both topotecan and irinotecan are active in relapsed 
SCLC. Topotecan is Food and Drug Administration (FDA)-approved for participants with SCLC 
with chemotherapy-sensitive disease after failure of first-line chemotherapy. 
Extrapulmonary small cell carcinoma is a distinct clinicopathologic entity that can arise in a wide 
range of extrapulmonary sites. These tumors have been described most frequently in the bladder, 
prostate, esophagus, stomach, colon and rectum, gallbladder, larynx, salivary glands, cervix, and 
skin. They are extremely rare and management of systemic disease with chemotherapy is patterned 
the approach used in SCLC[16].
Camptothecins are an active drug class in SCLC. Both irinotecan [17] and topotecan [18] are used 
in the first and second line setting respectively as part of standard care. 
Drugs that target DNA damage response (DDR), including PARP inhibitors, have shown 
promising activity against SCLC in pre-clinical models and in early clinical trials. Proteomic 
profiling of a large panel of SCLC cell lines led to the observation that PARP1, Chk1, and several 
other DNA repair proteins are expressed at high levels in SCLC [19]. These studies also confirmed 
PARP1 overexpression in participant tumors at the protein level by immunohistochemistry and at 
the mRNA level. Based on this finding, several PARP inhibitors were tested in pre-clinical models 
of SCLC. Olaparib, rucaparib, and talazoparib (BMN-673) all demonstrated striking single agent 
activity in a majority of SCLC cell lines tested. Furthermore, the addition of a PARP inhibitor to 
standard chemotherapies (e.g., cisplatin, etoposide and/or topotecan) and radiation further 
potentiated their effect [20]. In animal models including xenografts and participant-derived 
xenografts (PDXs), talazoparib has demonstrated significant anti-tumor activity as a single agent, 
comparable or superior to cisplatin [21]. 
Following these observations, several clinical trials were initiated to investigate the effects of 
PARP inhibition in SCLC participants. Single-agent talazoparib was tested in an expansion cohort 
of participants with platinum-sensitive SCLC relapse [22]. Two of 23 participants had a partial 
response (PR; objective response rate (ORR), 9%, with duration of response 12.0 and 15.3 weeks, 
respectively), and a further 4 had SD lasting at least 16 weeks (CBR, 26% ≥16 weeks). Additional 
studies have also evaluated the combination of PARP inhibitors and DNA damaging chemotherapy 
in SCLC. Based on phase 2 data showing activity of temozolomide (TMZ) in relapsed SCLC and 


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14
preclinical data demonstrating activity of TMZ in combination with PARP inhibitors [23], clinical 
trials have tested this combination in SCLC. In one study [24], 104 relapsed SCLC participants 
were randomly assigned 1:1 to oral veliparib or placebo plus temozolomide. Four-month PFS and 
median OS did not differ between the two arms, whereas a significant improvement in ORR was 
observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in 
participants receiving TMZ/veliparib. 
In preclinical SCLC models, PARP inhibition has been reported to down regulate key components 
of the DNA repair machinery and enhance the efficacy of chemotherapy [19]. PARP inhibition 
sensitizes cancer cells both to cytotoxic chemotherapy, such as alkylators (temozolomide, 
cyclophosphamide) or camptothecins (irinotecan, topotecan) and to ionizing radiation - all of 
which induce DNA damage requiring base excision repair (BER) [25]. PARP inhibitors are highly 
effective in combination with camptothecins in tumors with and without defects in homologous 
recombination [26-29]. The Pommier laboratory has demonstrated highly synergistic activity of 
olaparib in combination with camptothecins [29]. They observed that the synergistic activity is due 
to its catalytic PARP inhibitory activity rather than due to trapping of PARP-DNA complexes. 
1.2.2
SN-38 and PLX038
SN-38 is the active metabolite of CPT-11 (irinotecan) that inhibits topoisomerase I and causes 
DNA strand breakage. As a specific DNA damaging agent, SN-38 enhances cell kill in tumors 
deficient in the DNA-damage response (DDR; e.g. BRCA1/2-deletions) and when combined with 
inhibitors of the DDR (e.g. PARP inhibitors). PLX038 (PEG40kDa~SN-38) is a 4-arms 40 kDa PEG 
that has SN-38 attached by a slowly cleavable releasable linker to the ends of each arm; the species-
independent in vivo release rate of SN-38 is very long - 350 hr. [30]. 
For complete safety and efficacy information, refer to investigator brochure.
1.2.2.1
Preclinical efficacy studies of PLX038 and PLX038A 
Although the renal clearance of PLX038 in the mouse was too rapid to allow its use in this animal 
model, preclinical pharmacology studies showed high antitumor activity – comparable or better 
than CPT-11 – in numerous xenografts in the nude rat. 
An analog of PLX038 – PLX038A – was designed to mimic human pharmacokinetics of PLX038 
in the mouse, and preclinical studies were performed using the BRCA1-deficient, TNBC MX-1 
xenograft the mouse. Single, nontoxic doses of PLX038A completely inhibited growth of MX-1 
tumors and shrank massive tumors to undetectable levels. Using PET-imaging studies of an 89Zr 
surrogate of PLX038, we showed that PEG40kDa~SN-38 accumulated to a very high ~15% ID in 
the tumor and remained there for long periods (t1/2~14 days). Hence, we envisioned that we could 
“pre-load” a tumor with PEG40kDa~SN-38, allow the drug to clear systemically, and then treat with 
a PARP inhibitor; here, only the tumor would be exposed to both drugs concomitantly, and marrow 
toxicity of the combination might not occur. When used in combination with sub-therapeutic QD 
dose PARP inhibitor, talazoparib, a single low sub-therapeutic dose of PLX038A (10% of single 
dose) caused complete tumor inhibition and shrinkage of large tumors. Importantly, when the same 
sub-therapeutic dose of PLX038A was administered as a single agent, followed by a systemic 
washout of drug (4-half-lives of renal elimination), administration of the same sub-therapeutic QD 
dose of PARP inhibitor caused complete growth inhibition. In these combination studies, we did 
not observe weight loss or marrow toxicity.


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1.2.2.2
Preclinical Toxicology of PLX038
Maximum tolerated dose (MTD)/dose range finding (DRF), acute dose, 14 day and 28 day repeat 
intravenous (IV) PLX038 dosing studies were conducted in rats and monkeys. Based on the dosing 
studies, the primary target organs are the bone marrow, gastrointestinal tract and skin. The monkey 
was the more sensitive species. 
In rats, single IV doses up to 1,000 mg/kg and repeat weekly injections up to 800 mg/kg was well-
tolerated. Rats that received repeat weekly injections of 800 mg/kg had decreased thymic weight 
and bone marrow hypocellularity attributed to PLX038. High doses of PLX038 caused decreases 
in clinical chemistries and hematology, increased aPTT and PT and decreased food consumption.
In monkeys, a single large IV dose of 1,000 mg/kg and repeat weekly injections of ≥ 600 mg 
caused lethality. Cause of death was uncertain. Bone marrow depletion with correlating changes, 
with or without evidence of secondary infections, were possible contributing factors to the deaths. 
Macroscopic multifocal red discoloration and acute inflammation of gastrointestinal organs were 
also noted, probably related to PLX038. 
In surviving monkeys, a dose-dependent increase in diarrhea was noted. All animals experienced 
decreases in clinical chemistries and hematology that were reversible. At autopsy, bone marrow 
hypocellularity, decreased thymic and spleen size were detected. Macroscopic changes in the 
gastrointestinal epithelium (inflammation, multifocal lesions) were also noted, thought to be 
caused by PLX038.
In the 4-week repeat dose study in monkey, small to large cornea pigmentation was observed in 
monkeys in all treatment groups at the end of the dosing period. In some cornea pigmentation 
persisted and was still present at the end of the recovery period. Two monkeys in the low dose 
(200 mg/kg) group that did not have cornea staining on Day 25 developed medium pigmentation 
on Day 50 suggesting a possible delayed effect. Due to the observation of cornea pigmentation in 
all treatment groups, no no-effect-level (NOAEL) could be determined in the 4-week repeat dose 
study. 
In both rats and monkeys, histopathology revealed mild to moderate vacuolation in several tissues. 
1.2.2.3
Phase 1 dose escalation of PLX038
The Phase 1 dose escalation trials are being performed in single-dose cohorts at MD Anderson, 
with Dr. Jaffer Ajani as PI, and Theradex Oncology as CRO. Table 4 shows the current study 
enrollment through Participant 38 (including 4 screen failure patients) and describes the dose level, 
cancer type, and other relevant information. To date in the Phase I study D15-11073, 34 patients 
have received PLX038 treatment at doses ranging from 115 mg/m2 to 3060 mg/m2 (corresponding 
to ~1 to 32 mg/m2 released SN38) q3w in 21-day cycles. The study is ongoing. 
Treatment emergent adverse events (TEAEs) during Study D15-11073 have been reported for all 
34 safety evaluable patients as of January 2022. The most common TEAEs have been reported for 
the system organ classes of gastrointestinal disorders (28 patients, 82.3%), metabolism and 
nutrition disorders (25 patients, 89.3%) and General System Disorders/Fatigue 11 patients 
(32.4%). PLX038-related TEAEs during Study D15-11073 have been reported for 25 patients 
(73.5%) from the safety evaluable population to date. Of the 25 patients with PLX038-related 
TEAEs, 11 patients (32.4%) had related TEAEs that were ≥Grade 3 in severity. The most common 
PLX038-related TEAEs were diarrhea (16 patients), nausea (14 patients), decreased appetite (13 


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16
patients), vomiting (11 patients), fatigue (10 patients), abdominal pain (5 patients), dehydration (4 
patients), hypokalemia (4 patients), neutrophil count decreased (4 patients), and colitis (3 patients).
Of the 34 patients in the safety evaluable population, 16 patients (41.1%) have reported serious 
adverse events (SAEs) during the study. The most common SAEs reported in the study are diarrhea 
(6 patients, 17.6%), abdominal pain (3 patients, 8.8%), and dehydration (3 patients, 8.8%). 
To date, there are 8 patients (23.5%) who have experienced serious adverse reactions (SARs) that 
were at least possibly related to study treatment.. Additionally, Patient 001-029 (enrolled in the 
2600 mg/m2 dose level), experienced Grade 3 diarrhea, which was considered a dose limiting 
toxicity (DLT), during Cycle 1, Day 13 that was definitely related to study therapy and resolved 
within 4 days of onset. Lastly, Patient 001-031 (enrolled in the 2300 mg/m2 dose level) 
experienced possibly related Grade 2 dehydration and definitely related Grade 3 diarrhea on Cycle 
1, Day 9. On Cycle 1, Day 13 the patient experienced possibly related Grade 4 dehydration and 
unrelated Grade 5 embolism, which had a fatal outcome. 
Table 2. Serious Adverse Events (N=34 Patients dosed, 16 patients affected *)
Patie
nt
Dose 
(mg/m
2)
Preferred Term 
(PT)
DLT 
Toxicit
y
Grade
Serious
Drug 
Relationsh
ip
Action 
Taken
Outcome of Event
001-
002
172
GI hemorrhage
No
2 - 
Moderate
Hospitalizati
on
Unrelated
None
Recovered/Resolved
001-
005
580
Apnea
No
5 - Fatal
Results in 
Death
Unrelated
None
Fatal
001-
005
580
Cardiac arrest
No
5 - Fatal
Results in 
Death
Unrelated
None
Fatal
001-
005
580
Sepsis
No
4 - Life 
threatening
Hospitalizati
on
Unlikely
None
Recovered/Resolved
001-
005
580
Upper GI hemorrhage
No
5 - Fatal
Results in 
Death
Unrelated
None
Fatal
001-
006
387
Biliary tract infection
No
4 - Life 
threatening
Hospitalizati
on
Unrelated
None
Recovered/Resolved
001-
007
580
Mental status changes
No
1 - Mild
Hospitalizati
on
Unrelated
None
Recovered/Resolved
001-
007
580
Peritonitis bacterial
No
3 - Severe
Hospitalizati
on
Unrelated
None
Recovered/Resolved
001-
014
3060
Gastric hemorrhage
No
3 - Severe
Hospitalizati
on
Unrelated
None
Recovered/Resolved
001-
015
3060
Malignant neoplasm 
progression
No
5 - Fatal
Results in 
Death
Unrelated
None
Fatal
001-
017
3060
Abdominal pain
No
3 - Severe
Hospitalizati
on
Possible
Dose 
Discontinue
d
Recovered/Resolved
001-
017
3060
Colitis
No
3 - Severe
Hospitalizati
on
Probable
None
Recovered/Resolved


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Patie
nt
Dose 
(mg/m
2)
Preferred Term 
(PT)
DLT 
Toxicit
y
Grade
Serious
Drug 
Relationsh
ip
Action 
Taken
Outcome of Event
001-
017
3060
Hypoalbuminemia
No
4 - Life 
threatening
Hospitalizati
on
Unrelated
Dose 
Discontinue
d
Not Recovered/ Not 
Resolved
001-
017
3060
Hypokalemia
No
3 - Severe
Hospitalizati
on
Possible
Dose 
Discontinue
d
Recovered/Resolved
001-
018
3060
Dehydration
No
3 - Severe
Hospitalizati
on
Definite
None
Recovered/Resolved
001-
018
3060
Diarrhea
No
3 - Severe
Hospitalizati
on
Definite
None
Recovered/Resolved
001-
018
3060
Sepsis
No
4 - Life 
threatening
Hospitalizati
on
Unrelated
None
Recovered/Resolved
001-
018
3060
Small intestinal 
obstruction
No
3 - Severe
Hospitalizati
on
Possible
Dose 
Discontinue
d
Recovered/Resolved
001-
019
3060
Abdominal pain
No
3 - Severe
Hospitalizati
on
Probable
None
Recovered/Resolved
001-
019
3060
Dehydration
No
3 - Severe
Hospitalizati
on
Definite
None
Recovered/Resolved
001-
019
3060
Diarrhea
No
3 - Severe
Hospitalizati
on
Definite
None
Recovered/Resolved
001-
019
3060
Hypotension
No
3 - Severe
Hospitalizati
on
Definite
None
Recovered/Resolved
001-
019
3060
Small intestinal 
obstruction
No
3 - Severe
Hospitalizati
on
Probable
None
Recovered/Resolved
001-
021
2800
Colitis
No
2 - 
Moderate
Hospitalizati
on
Definite
None
Recovered/Resolved
001-
021
2800
Diarrhea
No
2 - 
Moderate
Hospitalizati
on
Definite
None
Recovered/Resolved
001-
021
2800
Hypokalemia
No
3 – Severe
Hospitalizati
on
Definite
None
Recovered/Resolved
001-
024
2600
Abdominal pain
No
3 - Severe
Hospitalizati
on
Unrelated
None
Recovered/Resolved
001-
024
2600
Enterocolitis
No
2 - 
Moderate
Hospitalizati
on
Possible
Dose 
Discontinue
d
Recovered/Resolved
001-
026
2600
Lung infection
No
3 - Severe
Hospitalizati
on
Unrelated
None
Recovered/Resolved


Abbreviated Title: PLX038 and Rucaparib
Version Date: 03/11/2024
18
Patie
nt
Dose 
(mg/m
2)
Preferred Term 
(PT)
DLT 
Toxicit
y
Grade
Serious
Drug 
Relationsh
ip
Action 
Taken
Outcome of Event
001-
029
2600
Diarrhea
Yes
3 - Severe
Hospitalizati
on
Definite
Dose 
Discontinue
d
Recovered/Resolved
001-
031
2300
Diarrhea
Yes
3 - Severe
Hospitalizati
on
Definite
Dose 
Discontinue
d
Not Recovered/ Not 
Resolved
001-
031
2300
Embolism
Yes
5 - Fatal
Results in 
Death
Unrelated
None
Fatal
* Patients may have experience more than one SAE
Three deaths have been reported to date, all of which were considered to be unrelated to study 
treatment. Patient 001-005 (enrolled in the 580 mg/m2 cohort) developed a fatal upper GI 
hemorrhage leading to cardiac arrest and apnea. Patient 001-015 (enrolled in the 3060 mg/m2 
cohort) died of malignant neoplasm progression. Patient 001-031 (enrolled in the 2300 mg/m2 dose 
level), experienced Grade 3 diarrhea (definitely related) and Grade 5 embolism (unrelated), which 
had a fatal outcome
To date,5 patients (14.7%) have been removed from the study (dose discontinued) due to a serious 
adverse event (SAEs): 
Table 3. Patients Discontinued Due to SAE
Patient
Dose 
mg/m2
Adverse
Event
DLT
Grade
Serious
Drug 
Relationship
Therapy 
Given
Action Taken
001-
017
3060
Hypokalemia
No
3
Hospitalization
Possible
Yes
Dose 
Discontinued
 
3060
Abdominal Pain
No
3
Hospitalization
Possible
Yes
Dose 
Discontinued
 
3060
Hypoalbuminemia
No
4
Hospitalization
Possible
Yes
Dose 
Discontinued
001-
018
3060
Small Intestinal 
Obstruction
No
3
Hospitalization
Possible
No
Dose 
Discontinued
001-
024
2600
Enterocolitis
No
2
Hospitalization
Possible
Yes
Dose 
Discontinued
001-
029
2600
Diarrhea
Yes
3
Hospitalization
Definite
Yes
Dose 
Discontinued
001-
031
2300
Diarrhea
Yes
3
Hospitalization
Definite
Yes
Dose 
Discontinued
 Of the 34 dosed patients in the safety evaluable population, 18 patients (52.9%) have reported 
SAEs during the study. The most common SAEs reported in the study are diarrhea (6 patients, 
18.2%), abdominal pain (3 patients, 9.1%), and dehydration (3 patients, 9.1%).
A total of 22 (64.7%) of 34 patients enrolled and dosed in the phase I trial experienced diarrhea. 
Diarrhea was less frequent at the lower doses; 4/10 (40%) patients who received lower doses (1300 
mg/m2 or lower) had diarrhea compared with 18/24 (75%) patients treated at higher doses (1730-
3060 mg/m2). Severe diarrhea was more frequent at the higher doses; all instances of diarrhea 
were mild at the lower doses, while 13 patients had moderate-severe diarrhea at the higher doses. 


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Version Date: 03/11/2024
19
Five patients developed neutropenia, including two patients with grade 4 events. All patients with 
neutropenia were treated at 2600 or 3060 mg/m2.
As of this report, the PLX038 dose of 3060 mg/m2 as a single agent has been identified as the 
maximal administered dose in the D15-11073 study, with associated dose limiting toxicities 
(DLTs) of Grade 4 neutropenia, and Grade 3 nausea, diarrhea, and small intestinal obstruction. 
Additionally, the intermediate doses of 2800 mg/m2 and 2600 mg/m2 were not tolerated as they 
caused Grade 3 diarrhea in the two patients treated at each dose level. In all, duration of diarrhea 
of Grades 1 to 3 experienced by 22 patients ranged from 1 to 35 days, lasting an average of 11 
days. The D15-11073 study continues in order to determine the recommended Phase II dose for 
single agent PLX038 administered on a q3w schedule.
In addition, because of the low liver exposure of SN-38 from PLX038, the metabolite SN-38G 
formed from UGT1A1 is low, with plasma SN-38-G/SN-38 = 0.3 ± 0.1. Hence, UGT1A1 activity 
is not expected to play a major role in disposition of PLX038; in recognition of the latter, the FDA 
has allowed full-dose PLX038 treatment of participants heterozygous in UGT1A1*28.  
Four patients remained on study without progression of disease for more than 3 months. Of note 
is participant 4. Beginning 06/16/14 this participant had multiple previous treatments including 
CPT-11 in 2015/16. He was treated with PLX038 from December 2016 through July 2018 and had 
a confirmed partial response. 
–
06/16/14- 07/23/14: FU/Xeloda/Docetaxel->CR
–
01/27-05/06/15: Herceptin/OxyPlt->SD
–
06/15-07/06/15: Xeloda->PD
–
10/13/15-6/29/16: Trastuzumab/FU/Irinotecan->SD
–
12/15/16- 07/2018: 387 mg/m2 PLX038 (at 10/02/17-> 38% LN decrease, PR).
   Table 4: Patient summaries
Pt. No.
Tumor Type
UGT Status
Date 
Enrolled
Dose 
Cohort
Dose 
Level
Date of 
first dose
Off-
treatment/Off-
study date
Months 
on 
therapy 
at 
Q3Wk
Reason off 
treatment
001-1
Rectal 
adenocarcinoma
Homozygous 
WT
4/15/2016
1
115 
mg/m2
4/15/2016
7/7/2016
2.5
PD
001-2
GE 
adenocarcinoma
Homozygous 
WT
6/30/2016
2
172 
mg/m2
6/30/2016
8/15/2016
1.5
PD
001-3
Rectal 
adenocarcinoma
Homozygous 
WT
10/18/2016
3
258 
mg/m2
10/18/2016
11/29/2016
1.5
PD
001-4
Esophageal 
Adenocarcinoma
Homozygous 
WT
12/14/2016
4
387 
mg/m2
1/3/2017
7/3/2018
18
PD
001-5
Adenocarcinoma 
of lower 
esophagus
Homozygous 
WT
12/7/2017
5
580 
mg/m2
12/7/2017
12/15/2017
0.5
NE due to 
early death 
due to 
underlying 
tumor.
001-6
Gastric cancer
Heterozygous
4/12/2018
4
387 
mg/m2
4/12/2018
5/24/2018
1.5
PD
001-7
Pancreatic 
cancer
Homozygous 
WT
4/23/2018
5
580 
mg/m2
5/3/2018
6/8/2018
1
PD
001-8
Pancreatic 
cancer
Heterozygous
4/25/2018
4
387 
mg/m2
5/9/2018
6/21/2018
1.5
PD


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Version Date: 03/11/2024
20
Pt. No.
Tumor Type
UGT Status
Date 
Enrolled
Dose 
Cohort
Dose 
Level
Date of 
first dose
Off-
treatment/Off-
study date
Months 
on 
therapy 
at 
Q3Wk
Reason off 
treatment
001-9
Colon cancer
Homozygous 
WT
8/14/2018
6
870 
mg/m2
8/14/2018
9/24/2018
1.5
PD
001-10
Esophageal 
Adenocarcinoma
Homozygous 
WT
9/27/2018
7
1300 
mg/m2
9/27/2018
1/10/2019
3.5
PD
001-11
Squamous cell of 
esophagus
Homozygous 
WT
11/26/2018
8
1730 
mg/m2
11/26/2018
2/18/2019
2.5
PD
001-12
 
Homozygous 
*28
 
 
 
0
SF
001-13
Gastric 
adenocarcinoma
Heterozygous 
intermed met
1/11/2019
9
2300 
mg/m2
1/17/2019
2/28/2019
1
PD
001-14
Esophageal 
Cancer
Heterozygous 
3/12/2019
10
3060 
mg/m2
3/14/2019
3/25/2019
0.5
Hospice
001-15
Esophageal 
Cancer
Heterozygous 
4/2/2019
10
3060 
mg/m2
4/15/2019
5/16/2019
1
Hospice
001-16
Esophageal 
Cancer
Heterozygous 
intermed met
5/16/2019
10
3060 
mg/m2
5/16/2019
8/26/2019
3.5
PD
001-17
Esophageal 
Cancer
Heterozygous 
5/30/2019
10
3060 
mg/m2
6/3/2019
7/30/2019
2
Intercurrent 
illness
001-18
Gastric 
adenocarcinoma
Heterozygous 
intermed met
7/16/2019
10
3060 
mg/m2
7/22/2019
8/14/2019
1
Unacceptable 
toxicity
001-19
adenocarcinoma
Homozygous 
WT
8/29/2019
10
3060 
mg/m2
9/5/2019
11/7/2019
2
PD
001-20
adenocarcinoma
Homozygous 
WT
8/29/2019
10
3060 
mg/m2
9/6/2019
10/18/2019
1.5
PI decision
001-21
Esophageal 
adenocarcinoma
Heterozygous 
2/27/2020
11
2800 
mg/m2
3/5/2020
4/16/2020
1.5
PD
001-22
Stomach 
adenocarcinoma
Heterozygous 
3/12/2020
11
2800 
mg/m2
3/16/2020
4/13/2020
1
PD
001-23
Esophageal 
adenocarcinoma
Heterozygous 
8/27/2020
12
2600 
mg/m2
8/31/2020
11/12/2020
2.5
PD
001-24
Colon cancer
Heterozygous 
9/1/2020
12
2600 
mg/m2
9/2/2020
8/7/2020
1
Intercurrent 
illness
001-25
Esophageal 
Cancer
Heterozygous 
10/2/2020
12
2600 
mg/m2
10/5/2020
1/20/2021
3.5
PD
001-26
Esophageal 
adenocarcinoma
Heterozygous 
10/29/2020
12
2600 
mg/m2
10/29/2020
12/7/2020
1.5
PI decision
001-27
Esophageal 
Cancer
Heterozygous 
12/16/2020
12
2600 
mg/m2
12/17/2020
1/5/2021
1
Unacceptable 
toxicity
001-28
solid tumor
Heterozygous 
*28
1/21/2021
12
2600 
mg/m2
 
0
SF
001-29
metastatic 
adenocarcinoma
Heterozygous 
2/24/2021
12
2600 
mg/m2
2/25/2021
3/12/2021
0.5
Unacceptable 
toxicity
001-30
solid tumor
Heterozygous 
4/2/2021
9
2300 
mg/m2
 
3/10/2021
0
SF
001-31
solid tumor
Heterozygous 
4/2/2021
9
2300 
mg/m2
4/7/2021
4/19/2021
0.5
Death
001-32
solid tumor
Homozygous 
WT
7/16/2021
9
2300 
mg/m2
 
7/29/2021
0
WOC/SF
001-33
gastric
Heterozygous 
*28
8/20/2021
9
2300 
mg/m2
8/26/2021
9/8/2021
0.5
WOC
001-34
solid tumor
 
10/14/2021
13
2000 
mg/m2
10/21/2021
11/11/2021
0.5
PI decision
001-35
solid tumor
Homozygous 
WT
11/3/2021
13
2000 
mg/m2
11/11/2021
12/27/2021
1.5
PD
001-36
solid tumor
Heterozygous 
*6
11/17/2021
13
2000 
mg/m2
11/18/2021
C3D15
on-study
001-37
solid tumor
Heterozygous 
2/3/2022
8
1730 
mg/m2
2/3/2022
C1D2
on-study
001-38
Solid tumor
 
2/9/2022
8
1730 
mg/m2
2/10/2022
on-study


Abbreviated Title: PLX038 and Rucaparib
Version Date: 03/11/2024
21
Table 5. Possibly related adverse events
Possibly Related Adverse 
Events
# of 
Participants 
Affected 
N=16*
# of Participants with AEs, Highest CTCAE 
Grade
# of 
Participants 
with 
Serious AEs
Anorexia
12
Gr 1 (7), Gr 2 (4), Gr 3 (1)
0
Nausea
11
Gr 1 (6), Gr 2 (4), Gr 3 (1)
0
Vomiting
8
Gr 1 (6), Gr 2 (2)
0
Fatigue
8
Gr 1 (3), Gr 2 (2), Gr 3 (3)
0
Abdominal Pain
4
Gr 1 (1), Gr 2 (2), Gr 3 (1)
0
Hypokalemia
3
G1 (2), Gr 3 (1)
0
Neutropenia
1
Gr 2 (1)
0
Anemia
1
Gr 1 (1)
0
Hypocalcemia
1
Gr 2 (1)
0
Hyponatremia
1
Gr 1 (1)
0
Mucositis
1
Gr 1 (1)
0
Constipation
1
Gr 1 (1)
0
Ocular Pruritus
1
Gr 1 (1)
0
Loss of Appetite
1
Gr 1 (1)
0
Nasal Congestion
1
Gr 1 (1)
0
Rash
1
Gr 1 (1)
0
Small intestinal obstruction
1
Gr 3 (1)
1
Weight loss
1
Gr 2 (1)
0
* Patients may have experience more than 1 SAE
Table 6 shows pharmacokinetic (PK) parameters of various administered doses of Q3Wk PLX038 
vs 350 mg/m2 QWk CPT-11 and two other SN-38 prodrugs, Sacituzumab govitecan and Enz2208. 
Of note are the following:

Most of the weight of PLX038 is due to the large 40 kDa PEG component; SN-38 content 
is only 3.5% of the total weight, and considering renal elimination of PLX038, the actual 
SN-38 present in vivo is only ~1% of the total weight. 

The MTD of pegamotecan, a related PEG-camptothecins analog was 7 g/m2 [31] some 3-
fold higher than the current dose of PLX038. We thus assume we could dose-escalate 3-
fold higher than the current dose without PEG-related toxicity, if necessary, to reach MTD.

At the current dose of 2.3 g/m2, the free SN-38 is equivalent to the SN-38 formed from the 
MTD of Q3Wk CPT-11; but, Cmax is ~50% lower, t1/2 is 10-fold longer, and AUC is over 
5-fold higher. The PK benefits of PLX038 vs CPT-11 appear favorable.


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Table 6. Human PK parameters of SN-38 from PLX038 vs other SN-38 prodrugs A
Total SN-38 B
Free SN-38 
delivered C
SN-38 t1/2
SN-38 Cmax
SN-38 C14d D
SN-38 AUC E
mg/m2/cycle
mg/m2/cycle
h (n )
nM (n)
nM
nM•h (n)
PLX038 Q3W
 
 
 
 
14
4
97 ± 11.4 (4)
22 ± 6.2 (6)
1
1,660 ± 560 (4)
21
6
91 ± 3.7 (2)
14± 4.7 (3)
2
1,756 ± 1071 (2)
31
9
90 (1)
24± 13 (2)
3
2,513 (1)
46
13
85 hr
30
2
4,000
62
17
~100 hr
46
3
6,126
82
23
~100 hr
68
8
11,356
107
32
118 ± 31 h
186 ± 88 
11.7 ± 1.3
17,820 ± 2550
CPT-11 Q3Wk F
 
 
 
 
227
23
~12 hr
143
 
2,000
Sacituzumab govitecan ADC (QWk x 2, 3 wk. cycle) [32, 33]
15
14
~20 hr
230
0.1
7,600
EZN-2208 (Q3W)
10
10
30 h
370
~0
4,600
A PK data of 2,300 mg/m2 not yet available; estimates were simulated from lower doses assuming 
t1/2 = 100 h for PLX038 and dose linearity of Cmax. 
B SN-38 ~3.5% by weight of PLX038. 
C Delivered free SN-38 is ~ ~30% of total SN-38.
D C14d are estimated from given parameters (below LLOQ). 
E AUC0-∞ values are calculated from the models. 
F From label. 
1.2.3
Rucaparib
Rucaparib is being developed as an antineoplastic agent. Nonclinical evaluation has demonstrated 
exquisite sensitivity of BRCA1 and BRCA2 homozygous mutant cell lines to rucaparib, which is 
attributed to PARP inhibition alone, and provides a rationale for the clinical assessment of 


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rucaparib as monotherapy in participants with hereditary (HRD) (germline) and acquired (somatic) 
deficiencies of BRCA1 and BRCA2. Clinical data indicate that benefit from treatment with a 
PARP inhibitor includes participants with a germline BRCA or somatic BRCA mutation and may 
extend to participants with other HRD alterations. This supports the investigation of PARP 
inhibitors such as rucaparib in a broader group of tumors with HRD (inclusive of BRCA and 
BRCA-like, as well other than BRCA mutations involved in HRD).
The first marketing authorization was granted in the United States (US) on 19 December 2016, for 
the treatment of patients with deleterious BRCA mutation (germline and/or -somatic) associated 
advanced ovarian cancer, who have been treated with 2 or more chemotherapies. Clovis voluntarily 
withdrew this indication in the US, Europe and GB in 2022 based on the detriment in overall 
survival (OS) observed for patients randomized to rucaparib versus chemotherapy.
Rucaparib is currently approved in the US for:

The maintenance treatment of adult patients with recurrent epithelial ovarian (EOC), 
fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) who are in response 
(complete or partial) to platinum-based chemotherapy.

The treatment of adult patients with a deleterious BRCA mutation (germline and/or 
somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have 
been treated with androgen-receptor-directed therapy and a taxane-based chemotherapy.
The withdrawal of the treatment indication for BRCA-mutant ovarian cancer patients did not affect 
the other approved rucaparib indications.
For complete safety and efficacy information, refer to investigator brochure.
1.2.3.1
Overview of Clinical Findings 
Phase 1, 2, and 3 clinical studies have or are being conducted to evaluate oral rucaparib in cancer 
participants. These studies have evaluated the PK (including the effect of food), metabolism, 
safety, and efficacy of rucaparib following oral administration at doses ranging from 40 mg QD to 
840 mg BID in participants with solid tumors. Results from a Phase 1 dose-escalation study 
determined 600 mg BID as the RP2D, while an MTD was not identified. Phase 2 and Phase 3 
clinical studies with oral rucaparib have been or are being conducted with the 600 mg BID dose 
and in participants with cancer associated with HRD.
1.2.3.2
Clinical Pharmacology
Assessment of rucaparib PK in cancer participants showed an approximate dose-proportional 
exposure after QD or BID dosing, rapid absorption with Cmax achieved within 1.5 to 6 hours. The 
oral bioavailability was 36%. Rucaparib was moderately bound to human plasma proteins in vitro. 
At a dose of 600 mg BID rucaparib, steady state was achieved after approximately 1 week. At the 
target clinical dose of 600 mg, a high-fat meal increased the Cmax and AUC0-24 of rucaparib by 
20% and 38%, respectively, and delayed the median Tmax by approximately 2.5 hours as compared 
with that under fasted conditions. The effect of food on rucaparib PK is not considered to be 
clinically significant, thus rucaparib can be taken with or without food.
Drug interactions with rucaparib as a substrate were assessed in a population PK analysis. CYP2D6 
phenotypes (poor metabolizers, intermediate metabolizers, normal metabolizers, and ultra-rapid 
metabolizers) and CYP1A2 phenotypes (normal metabolizers and hyper inducers) did not 
significantly impact the steady-state exposure of rucaparib at 600 mg BID. Current smokers had 


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overlapping rucaparib exposures as compared to nonsmokers and former smokers. Collectively, 
the results suggest that CYP1A2 and CYP2D6 play limited role in rucaparib metabolism in vivo, 
and no rucaparib dose adjustment is needed when concomitantly administered with CYP 
inhibitors.
Concomitant treatment with proton pump inhibitors (PPIs) showed no clinically significant effect 
on rucaparib PK. No dose modification of rucaparib is required for participants who are receiving 
concomitant treatment with a PPI.
Results from Study CO-338-044 indicated that rucaparib, at 600 mg BID, moderately inhibited 
CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and showed no clinically significant 
effect on P-glycoprotein (P-gp). Caution should be exercised in the concomitant use of drugs that 
are substrates of the above CYP enzymes with narrow therapeutic windows.
Results from the mass balance and metabolite profiling study CO-338-045 showed rucaparib 
excretion primarily in feces, followed by urine. M324 derived from oxidation of rucaparib was the 
major metabolite identified. Other metabolic pathways included N-demethylation, N-methylation, 
and glucuronidation. Plasma rucaparib showed a T1/2 of 24 hours.
Preliminary PK data from prostate cancer participants (Study CO-338-052, TRITON2) are 
comparable with the data from ovarian cancer participants (Study CO-338-014, ARIEL3) 
suggesting a lack of PK difference between male and female participants.
1.2.3.3
Efficacy
The US approval of rucaparib for the treatment of women with relapsed BRCA-mutated (inclusive 
of germline and somatic BRCA mutations) ovarian cancer was based on pooled data for 106 
participants enrolled in either Part 2A of Study CO-338-010 (n = 42) or Part 1 or Part 2 of Study 
CO-338-017 (ARIEL2) (n = 64) who met the following criteria: received at least 1 dose of 
rucaparib 600 mg; received at least 2 prior chemotherapy regimens, including at least 2 platinum-
based regimens, and had a deleterious BRCA1/2 mutation (germline BRCA1/2 mutation in Study 
CO-338-010; germline or somatic BRCA1/2 mutation in Study CO-338-017 [ARIEL2]). In the 
integrated efficacy population, the investigator-assessed confirmed ORR per RECIST v1.1 was 
53.8% (95% CI, 43.8-63.5), and the median duration of response was 9.2 months (range, 1.7-9.8; 
95% CI, 6.6-11.6). For the secondary endpoint of investigator-assessed confirmed response per 
combined RECIST and GCIG CA-125 criteria, the ORR was 70.8% (95% CI, 61.1%-79.2%). 
Participants who were sensitive to their most recently administered platinum regimen had a higher 
ORR (65.8%; 95% CI, 54.3%-76.1%) than those who were resistant (ORR = 25.0%; 95% CI, 
8.7%-49.1%) or refractory (ORR = 0%; 95% CI, 0.0-41.0%) to their most recent platinum regimen. 
The PFS rate at 6 and 12 months was 79.0% and 41.0%, respectively.
Rucaparib efficacy in the maintenance setting was demonstrated in 564 participants randomized 
in Study CO-338-014 (ARIEL3). Rucaparib maintenance treatment significantly improved PFS 
compared with placebo in all primary analysis groups of participants with recurrent ovarian 
carcinoma after a complete or partial response to platinum-based therapy. The median PFS in the 
BRCA population was 16.6 months (95% CI, 13.4-22.9) for the rucaparib-treated participants and 
5.4 months (95% CI, 3.4-6.7) for the placebo group. The median PFS in the HRD population was 
13.6 months (95% CI, 10.9-16.2) for rucaparib-treated participants and 5.4 months (95% CI, 5.1-
5.6) for the placebo group. The median PFS in the intention to treat (ITT) population was 10.8 
months (95% CI, 8.3-11.4) for the rucaparib group and 5.4 months (95% CI, 5.3-5.5) for the 
placebo group. Overall, rucaparib as maintenance treatment reduced the risk of progression by 


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63.5% (HR 0.365 [95% CI, 0.295-0.451]; p < 0.0001) in the ITT population, demonstrating a 
strong treatment effect over placebo. Analysis of non-nested, non-overlapping participant 
subpopulations indicate that the significant improvement in PFS observed in the ITT population 
was not driven only by the HRD or BRCA subpopulations. Nearly half (44.6%) of the participants 
in the rucaparib group showed benefit at 1 year compared to 8.8% in the placebo group. At 18 and 
24 months, 32.0% and 26.0%, respectively, of participants who received rucaparib were still 
progression-free compared to 5.8% and 2.6% in the placebo group.
1.2.3.4
Safety
INTEGRATED SAFETY ANALYSIS FOR OVARIAN CANCER
Pooled safety data in the treatment setting are provided as of the 31 December 2017 visit cut-off 
for ovarian cancer participants in the ongoing Studies CO-338-010 (All Parts) and CO-338-017 
(ARIEL2; both Parts 1 and 2), in which 565 participants with relapsed ovarian cancer received 600 
mg BID rucaparib. Safety data in the maintenance setting are provided as of the 31 December 2017 
visit cut-off for Study CO-338-014 (ARIEL3), in which a total of 561 participants have been 
treated (372 participants in the rucaparib group and 189 participants in the placebo group). Pooled 
safety data from the treatment setting as well as safety data in the maintenance setting are presented 
in Table 7.
Table 7: Incidence of TEAEs (All Causality; All Grades, Grade ≥ 3) Reported in ≥ 20% of 
Participants - Safety Population


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26
In participants with ovarian cancer who received 600 mg BID rucaparib in pooled Studies CO-
338-010 and CO-338-017 (treatment setting), as well as in Study CO-338-014 (maintenance 
setting), the most common TEAEs reported were primarily mild to moderate (Grade 1-2) in 
severity and include gastrointestinal disorders (nausea, vomiting, diarrhea, constipation, and 
abdominal pain), asthenia/fatigue, decreased appetite, and dysgeusia. The most common TEAE ≥ 
Grade 3 include anemia/decreased hemoglobin, ALT/AST increased, neutropenia/decreased ANC, 
and asthenia/fatigue.
Effects on cardiac channel activity in vitro and a comprehensive assessment of the effects of 
rucaparib on ECG parameters in cancer participants demonstrated a low risk of cardiac effects by 
rucaparib.
The laboratory abnormalities reported in Study CO-338-014 (ARIEL3) were consistent with the 
TEAEs, with decreased hemoglobin, increased ALT, increased AST, and increased serum 
creatinine, most common in participants in the rucaparib group. Decreased platelets, neutrophils, 
leukocytes, lymphocytes, increased alkaline phosphatase and increased cholesterol were observed 
to a lesser extent.
ALT/AST elevations occurred early in treatment (i.e., by Day 1 of Cycle 2) and then resolved or 
stabilized over time. Treatment with rucaparib was continued at either the initial 600 mg BID dose 
or a lower dose. Elevations in ALT/AST were generally not accompanied by a concomitant 
elevation in bilirubin. Continued dosing with rucaparib in the presence of Grade 3 ALT/AST 
elevations is permitted if there are no other signs of liver toxicity.
Creatinine elevations were also observed early in treatment (i.e., by Day 1 of Cycle 2) and then 
stabilized with continued rucaparib treatment.
PRELIMINARY SAFETY ANALYSIS FOR PROSTATE CANCER
Safety data are provided as of the 06 March 2018 visit cut-off for prostate cancer participants in 
the ongoing Study CO-338-052 (TRITON2), in which 52 participants with mCRPC received 600 
mg BID rucaparib. The safety profile of rucaparib in the mCRPC participant population is 
consistent with the safety profile in ovarian cancer participants. The most common TEAEs 
reported were primarily mild to moderate (Grade 1-2) in severity and include gastrointestinal 
toxicities (nausea, constipation, vomiting, diarrhea), asthenia/fatigue, decreased appetite, 
anemia/decreased hemoglobin, ALT/AST increased, and dizziness. The most common TEAEs ≥ 
Grade 3 include anemia/decreased hemoglobin, ALT/AST increased, thrombocytopenia/decreased 
platelets, nausea, and hypophosphatemia.
1.2.3.5
Efficacy and safety update 
Studies CO-338-017 (ARIEL2) & CO-338-014 (ARIEL3)
The ARIEL program is evaluated rucaparib in patients with relapsed ovarian cancer. Study CO-
338-017 (ARIEL2) was a 2-part, single-arm, open-label, Phase 2 study of rucaparib as treatment 
for relapsed high-grade ovarian cancer. The primary purpose of the study was to determine a 
molecular signature of HRD associated with a response to rucaparib in patients with relapsed 
disease. Efficacy data from Part 1 (n = 204 patients) indicated that rucaparib led to clinically 
meaningful and durable responses in patients whose tumor contained a BRCA1/2 mutation or HRD 
(BRCA-like molecular signature), demonstrating that benefit from PARP inhibitor treatment 
extended beyond patients with a BRCA mutation. 


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In Study CO-338-017, Part 2 (n = 287 patients), efficacy data in more heavily pretreated patients, 
predominantly with platinum-resistant/refractory disease, as compared to patients in Part 1, 
indicated the greatest activity in patients with a tBRCA mutation. However, there was greater 
activity in patients in Part 1 who had earlier-line platinum-sensitive disease as compared to the 
patients in Part 2 who were more heavily pretreated. The optimized molecular HRD signature from 
Study CO-338-017 was prospectively applied to the primary analysis of Study CO-338-014 
(ARIEL3), an ongoing, randomized, double-blind, Phase 3 study of rucaparib versus placebo as 
switch maintenance treatment in patients with platinum-sensitive, relapsed, high-grade ovarian 
cancer (N = 564 enrolled patients). 
Study CO-338-043 (ARIEL4)
Efficacy data indicated a highly statistically significant difference in invPFS between rucaparib 
and placebo for each of the 3 primary efficacy analysis populations (tBRCA, HRD, and ITT). The 
TEAEs reported with rucaparib treatment are consistent with those previously reported in open-
label, non-randomized studies of rucaparib. The Phase 3 Study CO-338-043 (ARIEL4) evaluated 
rucaparib versus chemotherapy as treatment for patients with relapsed high-grade ovarian cancer 
associated with a deleterious BRCA1/2 mutation (N = 349 enrolled patients) and served as a 
confirmatory study for third-line+ treatment of BRCA-mutant ovarian cancer patients. Study CO-
338-043 met the primary endpoint of invPFS, demonstrating a benefit for rucaparib treatment 
compared with active, standard-of-care chemotherapy. The safety profile was consistent with the 
safety profile in currently approved maintenance and treatment indications, and the tolerability of 
rucaparib was comparable with standard-of-care chemotherapy. 
Final data analyses for Study CO-338-043 showed detrimental effect in terms of overall survival 
(OS) for patients randomized to rucaparib versus chemotherapy. The OS results were heavily 
confounded by a high rate of cross-over to rucaparib for patients initially randomized to the 
chemotherapy arm (close to 90% of all patients in ARIEL4 received rucaparib after randomization 
or crossover), as well as the post-progression subsequent treatments and was largely driven by 
patients with platinum-resistant disease.
Study CO-338-087 (ATHENA)
Study CO-338-087 (ATHENA) is an ongoing, randomized, double-blind, placebo-controlled 
Phase 3 study evaluating rucaparib as monotherapy (ATHENA-MONO) and in combination with 
nivolumab (vs. nivolumab; ATHENA-COMBO) as maintenance treatment following response to 
first-line platinum-based chemotherapy in patients with newly diagnosed ovarian cancer who have 
also undergone cytoreductive surgery. 
TRITON Program
The TRITON program is evaluating rucaparib efficacy in a Phase 2 (CO-338-052 [TRITON2]) 
and a Phase 3 (CO-338-063 [TRITON3]) study of mCRPC. Study CO-338-052 (Phase 2) is 
evaluated rucaparib monotherapy for the treatment of mCRPC associated with evidence of HRD, 
with an emphasis on defects in BRCA1/2 and ATM genes, and an exploratory evaluation of other 
HRR gene mutations, in patients who have received prior AR-directed therapy and a taxane. 
Results from the final safety analysis of patients with mCRPC (n = 277) in Study CO-338-052 are 
consistent with those reported for ovarian cancer patients. Rucaparib PK exposure in prostate 
cancer patients is comparable to that in ovarian cancer patients (Study CO-338-014), suggesting 
no sex-related PK difference of rucaparib. Study CO-338-063 (Phase 3) is a randomized study 


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28
evaluating rucaparib monotherapy versus physician’s choice (abiraterone acetate, enzalutamide, 
or docetaxel) for the treatment of mCRPC patients with a BRCA1/2 or ATM mutation who have 
received prior treatment with AR-directed therapy but have not yet received taxane-based 
chemotherapy in the castration-resistant setting. Additionally, a Phase 1b Study CO-338-107 
(RAMP) is ongoing to evaluate the PK, safety, tolerability, and preliminary efficacy of rucaparib 
in combination with other anticancer therapies in patients with mCRPC. 
Frequently reported TEAEs in the ovarian and prostate cancer populations included GI toxicities 
(eg, nausea and vomiting), myelosuppression, asthenia/fatigue, and elevated ALT/AST. These 
toxicities were successfully managed by treatment interruption or dose reduction and/or supportive 
care. 
Study CO-338-010
Study CO-338-010 evaluated rucaparib in patients with any solid tumor that progressed on 
standard treatment (Part 1; Phase 1), patients with relapsed ovarian cancer associated with a BRCA 
mutation (Parts 2A and 2B; Phase 2), and patients with relapsed solid tumor and a BRCA mutation 
(Part 3; Phase 2). In Part 1, 56 patients with advanced solid tumors received oral rucaparib at dose 
levels of 40 mg to 500 mg QD and 240 mg to 840 mg BID. The PK of rucaparib was approximately 
dose-proportional in the tested dose range. In Parts 2A and 2B, clinically meaningful and durable 
responses to rucaparib were observed in patients with a gBRCA1/2 mutation. In Part 3 (Phase 2), 
the PK of a 300 mg dose strength tablet and a total dose of 600 mg rucaparib were characterized 
in patients with a solid tumor with a known deleterious BRCA1/2 mutation. The effect of food on 
rucaparib PK was also evaluated. At the target clinical dose of 600 mg, a high-fat meal increased 
the Cmax and AUC0-24 by approximately 20% and 38%, respectively, and delayed the median 
Tmax by approximately 2.5 hours. The effect of food on rucaparib exposure was not deemed 
clinically significant; rucaparib may be taken with or without food. 
Study CO-338-081
Study CO-338-081 (RUCA-J) is an ongoing study. The Phase 1 study evaluated the safety and PK 
of rucaparib in patients with a previously treated solid tumor, to establish the RD in Japanese 
patients. The safety, tolerability, and PK of the RD in this study is being evaluated in Japanese 
patients who had progressed on standard treatment and had recurrent HGSOC (no gene mutation 
required), BRCA1/2-mutated breast cancer, or other solid tumor with evidence of a BRCA1/2 or 
other HRR gene mutation. At 600 mg BID, steady-state Cmax and AUC of rucaparib were slightly 
higher than that in Western patients, but the difference was not considered clinically significant, 
thus no adjustment in the starting dose is considered necessary. 
Phase 1 Clinical Pharmacology Studies 
Phase 1 clinical pharmacology studies were conducted in patients with advanced solid tumors. 
Results from the completed DDI portion (Part 1) of Study CO-338-044 indicated that rucaparib, 
at 600 mg BID, moderately inhibited CYP1A2, weakly inhibited CYP2C9, CYP2C19, and 
CYP3A, and marginally inhibited P-gp. In Part I of Study CO-338-095 (a DDI study), rucaparib 
600 mg BID caused 29% increase in Cmax and 35% increase in AUCinf of oral rosuvastatin (a 
BCRP substrate), and 43% and 56% increases in AUClast of the oral contraceptives 
ethinylestradiol and levonorgestrel, respectively. In Study CO-338-107, concomitant dosing of 
rucaparib with a strong CYP3A4 inducer enzalutamide showed no change in trough PK of either 
rucaparib or its metabolite M324 (formation is mediated by CYP3A4), indicating that CYP3A4 


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29
has no significant effect on rucaparib PK. Results from the completed mass balance and metabolite 
profiling portion (Part 1) of Study CO-338-045 following a single oral dose of [14C]-rucaparib 
showed that rucaparib was predominantly excreted in feces (71.9% of recovered 14C 
radioactivity), followed by urine (17.4% of recovered 14C radioactivity). Oxidation, N-
demethylation, N-methylation, and glucuronidation were the major metabolic pathways for 
rucaparib, with M324, derived from oxidation of rucaparib, identified as the most abundant 
metabolite. In Study CO-338-078 (Part I), patients with moderate hepatic impairment showed 
similar Cmax but 44.6% higher AUCinf after a single oral dose of 600 mg rucaparib as compared 
to patients with normal hepatic function. 
1.2.4
Rationale for this study
Top1 inhibitors are a class of chemotherapeutic agents that inhibit DNA replication and induce 
DNA strand breaks that require PARP for their repair. As such, PARP inhibition is highly 
synergistic in combination with Top1 Inhibitors [29]. In BRCA-wt participants, where PARP 
inhibitor monotherapy treatment does not demonstrate synthetic lethality, the ability to improve 
tumor response may be achieved with combination therapy. It is hypothesized that combining 
PARP inhibitors with Top1 inhibitors will result in increased efficacy in the clinic compared to 
either agent alone.
While the combination of PARP inhibitor and Top1 inhibitor is expected to be synergistic, dose-
limiting toxicities have prevented this combination from being dosed at high doses of each drug, 
thereby limiting its potential clinical utility. The advantage of dosing with PLX038 compared to 
conventional Top1 inhibitor is the extended PK profile and prolonged local tumor exposure of SN-
38. Since SN-38 is cleared more quickly from normal tissues than from tumor, it is hypothesized 
that delayed dosing of rucaparib (i.e. starting rucaparib dosing a few days after PLX038 
administration) will allow for the expected window of maximum SN-38-induced toxicity to pass 
in the absence of concurrent rucaparib toxicity. However, the tumor levels of SN-38 are predicted 
to be sustained upon subsequent rucaparib dosing, therefore maintaining the ability of both drugs 
to act on tumor tissue simultaneously. 
The primary hypothesis for the proposed study is that a tolerable combination of PLX038 plus 
rucaparib can be identified using a dose-escalation strategy that incorporates dose scheduling (i.e. 
intermittent dosing of rucaparib as opposed to continuous dosing). 
The secondary hypothesis is that the combination of PLX038 plus rucaparib is more efficacious 
than either agent alone. The hypothesis that biomarkers will predict participant response to 
treatment will be investigated in an exploratory manner in two ways: markers of drug sensitivity 
and resistance will be measured pre-treatment, and pharmacodynamic markers will be measured 
post-treatment.
The starting dose of rucaparib (400 mg BID) is ~66% of its full dose (600 mg BID) and the starting 
dose of PLX038 (1,300 mg) is about 40% of its MTD (3,060 mg), a sufficiently low enough dose 
to ensure the safety as well as potential for enhanced efficacy. As discussed in the preclinical 
efficacy section of protocol 1.2.2.1 when used in combination with sub-therapeutic QD dose PARP 
inhibitor, talazoparib, a single low sub-therapeutic dose of PLX038A (10% of single dose) caused 
tumor shrinkage in TNBC xenograft models. Administering the PARP inhibitor with a 48 hour 
window after PLX038 will also likely minimize overlapping AEs of myelosuppression.


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2
1.2.5
Rationale for Amendment to Change Dose-Escalation Strategy (Amendment Version 
Date: 03/19/2021)
Topoisomerase 1 inhibitors such as PLX038 damage DNA and are synergistic in combination with 
DNA damage response inhibitors (DDRi) such as PARP inhibitors including rucaparib; however, 
synergism is observed in both anti-tumor and toxic effects. Indeed, clinical trials of irinotecan and 
a PARPi inhibitor have shown both activity and toxicities and both drugs required significant dose 
reductions from their MTD [34-37]. Notably, in all such studies schedules were such that both 
DNA damaging agent and were PARPi concomitantly administered, so maximal systemic 
exposure of both drugs occurred concurrently and without tumor selectivity. One approach to 
achieve selective tumor inhibition involves an innovative "gapped-schedule" [38] (Figure 3A) and 
use of a tumor-targeted DNA damaging agent. Here, the tumor-targeted PLX038 is administered 
first, and allowed time (a “gap”) to accumulate in the tumor and clear from the normal tissue. Then, 
rucaparib is introduced to prevent repair of DNA damaged by the SN-38 released from PLX038 
entrapped in the tumor.
PLX038 is long-acting PEGylated prodrug of SN-38 (Figure 1), the active metabolite of irinotecan 
(CPT-11) and payload of the antibody drug conjugate (ADC) Troveldy which is a potent inhibitor 
of Topoisomerase 1 and causes DNA damage [30]. The nano carrier (NC) drug conjugate – 
designated PLX038 – is composed of a 4-arm 40 kDa PEG carrier containing SN-38 moieties 
attached to the ends of each arm. The prodrug slowly releases SN-38, and has long species-specific 
elimination t1/2 values of ~20 hr in mice and ~5 days in humans. The 4-ARM PEG40kDa provides a 
neutral, highly flexible, long half-life nanocarrier with a hydrodynamic diameter of about 15 nm, 
in accord with ideal properties proposed for nanocarrier tumor accumulation by EPR [39].
Figure 1. Depiction of PLX038, a slow releasing prodrug of SN-38.
The pharmacokinetics of 89Zr-labeled surrogates of PLX038 in tumor xenografts and various 
normal tissues was studied by PET imaging (Figure 2)[40]. The observed concentration vs time 
profiles for normal tissues shows a high uptake at the earliest time of measurement, followed by 
an apparent monophasic loss and disappearance from the tissues. The nanocarrier is initially lower 
in tumors than in normal tissues because of poor vascularization of the tumor. The NCs in tumors 
then increases to a very high 10%–14% of the initial dose by approximately 4 days, with a t1/2 of 
uptake of 2- to 3 days, associated with the long circulation time of the PEG conjugate and resultant 
high duration of tumor exposure to the conjugate. Then, the nanocarriers efﬂux from the tumor 
much more slowly than from other tissues, with t1/2 values of 300- to 400 hours or up to 5-fold 
slower than from other tissues. Importantly, at periods longer than approximately 3 days the PEG 
conjugates are at signiﬁcantly higher concentration in tumor than in other tissues. Using PLX038, 
it has been shown that within the tumor environment SN-38 is slowly released over periods of 
several weeks, substantially increasing tumor exposure to the active drug [41]. 
SN-38
SN-38
SN-38
SN-38


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31
Figure 2. C vs t plot of accumulation of PLX038 surrogates in normal tissue and tumor [40].
Thus, the primary hypothesis of the study is that a tolerable combination of PLX038 plus rucaparib 
can be identified using a gapped schedule. The secondary hypothesis is that the combination of 
PLX038 plus rucaparib is more efficacious than either agent alone. If properly designed, the 
gapped-schedule ensures that when rucaparib is introduced, only the tumor would be exposed to 
both drugs, while normal tissues would be only exposed to the rucaparib. Clearly, the success of a 
gapped schedule will depend on a) achieving satisfactory tumor accumulation of both drugs, b) 
achieving the correct time gap between treatment with drug to achieve an optimal balance of 
efficacy and toxicity.
A
B
Figure 3. A) Rationale for gap-scheduling combination therapies with tumor-targeted 
topoisomerase 1 inhibitors (TTTi) such as PLX038 and DNA damage response inhibitors (DDRi, 
such as PARPi). The TTTi given on day 1 of each cycle initially produces DNA damage both in 
normal and tumor tissues (brown area). However, after a time gap, the TTTi is selectively retained 
and releases SN-38 predominantly in tumor tissues (green area). Treatment with the DDRi is then 
initiated (red arrows) while PLX038 is present in the tumor tissues but not in normal tissues. Such 
"gap-schedule" should avoid overlapping toxicity for normal tissues. B) Gap schedule dosing in 
MX-1 Xenograft BRCA1 deficient TNBC: PLX038 single dose; then 4 day washout (drug remains 
in tumor by enhance permeability retention (EPR)); then daily PARPi talazoparib.
Evidence for the success of gapped-scheduling has been obtained in preclinical models (Figure 
3B). Here, a single dose of PLX038A (PLX038 modified to mimic human PK of PLX038 in the 
0
24
48
72
96
120
144
168
192
216
0
5
10
15
20
25
30
Hours
%ID/mL
Brain
Heart
Liver
Kidney
Tumor
Tumor


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32
mouse) followed a gap of 4 days to allow systemic clearance of the PLX038A, followed by daily 
PARPi causes complete tumor suppression without weight loss or change in blood counts; the 
remarkable efficacy was not seen with the same doses of either drug alone. 
Data from dose level 1 demonstrates that PLX038A and rucaparib administered at 48-hour gap 
induces GI adverse events which precludes long-term administration of the combination, despite 
evidence of anti-tumor activity. The following modifications were considered to the dose 
escalation schema: a) dose lowering of the rucaparib (currently included in the protocol as dose 
level -1), or b) increase in the time-gap between dosing of PLX038 and the rucaparib. Dose 
lowering of rucaparib could reduce toxicity, but it may also reduce efficacy; increase in the time-
gap between dosing could retain efficacy but reduce toxicity. We believe there are good 
justifications for either approach.
There are several reasons why an increased gap may be preferable to dose modifications:
1. The current gap may not be optimal for tumor accumulation of PLX038. In rodent models, the 
tmax for tumor accumulation of PLX038 is ~100 hrs [40]. If similar in humans, the 48 hr gap 
may not be sufficient to allow maximal tumor uptake to take maximum advantage of the 
highest tumor/systemic PLX038 before BID rucaparib dosing is initiated. 
2. The efflux of PLX038 from xenograft tumors is extremely slow compared to normal tissues, so 
an increased gap time may not affect efficacy (tumor retention of PLX038) but could reduce 
toxicity (reduced drug in tox target tissue). The relative accumulation and efflux rates of 
PLX038 from human clinical tumors is unknown, however the underlying factors responsible 
for accumulation/slow efflux in xenografts (i.e. increased vasculature pore size, poor 
lymphatics, high interstitial pressure) are present in all solid tumors. In the absence of targeted 
uptake, tumor accumulation is driven by the concentration of PLX038 in the blood, with the 
maximum tumor concentration being determined by the ratio of influx/efflux rates; lowering 
the administered dose will lower the absolute concentration of PLX038 in the tumor and thus 
decrease antitumor activity. Given the slow efflux from the tumor relative to clearance from 
the systemic circulation, however, increasing the gap between administration is expected to 
have minimal effect on the intratumoral level of PLX038 while more significantly lowering 
the level of PLX038 in non-target tissues at the onset of PARPi dosing. This argues that the 
dose of PLX038 should remain at its current level, or be increased if possible, while increasing 
the delay between administration of PLX038 and PARPi.
3. The PK for SN-38 released from PLX038 in the human shows a t1/2 = 120 h, so increasing the 
gap from 2 to 5 days should not greatly affect tumor exposure but significantly reduce systemic 
exposure. The systemic SN-38 at the current gap of 48 hr is 76% of the ~55 nM Cmax, while at 
a gap of 120 h (5 days) the systemic SN-38 would be decreased to 50% of Cmax (or ~27 nM). 
While the tumor accumulation of PLX038 will remain unchanged due to the invariant dose 
and slow exit from the tumor, the systemic level of SN-38 at the time the PARPi is introduced 
will be reduced ~1.5-fold upon changing from a 2 to 5 day gap schedule. This is anticipated to 
reduce systemic toxicity with less effect on antitumor efficacy.
4. The current gap may not be sufficient to allow optimal elimination of PLX038 from toxicity 
target organs (e.g. intestinal epithelial cells) by the time PARPi is administered. Unlike the 
SN-38 formed from CPT-11 which shows high liver/GI-exposure (as evident from high SN-
38G/SN-38), the SN-38 from PLX038 has very low liver/GI exposure (as evident from low 
SN-38G/SN-38) [30, 42]; indeed, at the dose of PLX038 used in the NCI trial, SN-38G is 


Abbreviated Title: PLX038 and Rucaparib
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33
barely detectable. Nevertheless, GI exposure to SN-38 released from PLX038 may contribute 
to the GI toxicity observed with rucaparib. As with SN-38, SN-38G from PLX038 in the human 
shows a t1/2 = 120 h. Hence, the GI exposure to SN-38 would be reduced ~2-fold upon changing 
from a 2- to 5 day gap schedule which should reduce GI toxicity. 
5. Dose reductions of rucaparib have not had an impact on GI adverse effects. Symptoms 
persisted despite reductions in all who required dose reductions. 
Based on the above considerations, the following dose levels were proposed (no longer applicable 
as of amendment version date 4/8/2022):
Dose level
PLX038 every 3 weeks, g/m2 
IV
Rucaparib, mg PO BID
Former dose level 1 
(completed)
1.3
400 mg, days 3-19
-1A
1.0
300mg, days 5-19
1A
1.3 
300mg, days 5-19
2A
1.3 
400mg, days 5-19
3A
1.3
600mg, days 5-19
1.2.6
Additional Summary Safety and Efficacy Results and Rationale for Further Changes to 
Dose Escalation Strategy (as of amendment version date: 04/08/2022)
A total of 8 patients were enrolled at dose level 1 [PLX038 1,300 mg/m2 (~50% MTD) and 
rucaparib 400 mg BID (66% recommended dose)] with a 48-hour window between PLX038 and 
rucaparib. Six of 8 patients are evaluable for DLT-assessment. One of six evaluable patients had 
hematologic DLT of febrile neutropenia, grade 4 thrombocytopenia, and inability to begin 
subsequent treatment in 21 days due to drug toxicity. Seven patients had non-DLT GI toxicity 
(most commonly abdominal discomfort, diarrhea, or nausea). In six cases, these symptoms 
required rucaparib dose reductions or interruptions. In general, these symptoms persisted after 
rucaparib dose reduction to 300 mg, and to 200 mg in one case. 
Of seven patients evaluable for efficacy, there were 3 progressive disease (PD), 2 stable disease 
(SD), 1 partial response (PR), and 1 complete response (CR). Of the two evaluable patients with 
known tumor homologous recombination deficiencies, there were 1 CR (ATM mutated breast 
adenocarcinoma, Figure 4) and 1 PR (germline TP53 and somatic BRCA1 mutated triple negative 
breast cancer, Figure 5), and both patients remained on treatment for 11.5 and 4.5 months 
respectively. Notably, the responding patients had previously progressed on topoisomerase and 
PARP inhibitors. Minor responses qualifying as RECIST stable disease were seen in two other 
patients. 


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34
Figure 4. Complete response in patient with ATM mutated breast adenocarcinoma and multiple 
prior therapies.
Figure 5. Tumor response (stable disease by RECIST -18%) in patient with germline TP53 and 
somatic BRCA1 mutated TNBC. 
In summary, data from dose level one demonstrated that, while there are clear signs of efficacy, 
several patients had intolerable GI toxicities, none of which have met the criteria for DLT. Based 
on a number of considerations (outlined in more detail in section 1.2.5), the protocol was amended 
to decrease the starting dose of rucaparib to 300 mg BID (dose level 1A) and increase the gap to 5 
days between PLX038 and rucaparib (amendment version 3/19/2021). 
Two subjects enrolled at new dose level 1A. Both subjects developed febrile neutropenia and 
enterocolitis related to both PLX038 and rucaparib and died (reported to the IRB as unanticipated 
Problems REF 563724 & 564323). A patient died likely due to neutropenic sepsis related to 
PLX038 and rucaparib and another patient's death was likely due to disease progression in the 
setting of neutropenic enterocolitis, related to study drugs. Both rucaparib and PLX038 are known 


Abbreviated Title: PLX038 and Rucaparib
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35
to be associated with neutropenia and infection. While neutropenic sepsis leading to death is an 
expected AE with the class of TOP1 inhibitors (such as SN38), these events are considered as 
unexpected for PLX038 from a regulatory perspective as they had not been previously reported 
with PLX038.
Samples for PLX038 pharmacokinetic analysis were drawn on Cycle 1 day 1 (C1D1) at the 
following time points: before PLX038 infusion, end of infusion (EOI) (+5 minutes), 2 (+/- 15 
minutes) hours, 4 (+/- 15 minutes) hours and 24 (+/- 30 minutes) hours post EOI, on C1D5 just 
before starting rucaparib, and on C2D1 before the next PLX038 infusion. Samples for rucaparib 
analysis were collected on C1D7 (optional): before rucaparib, 2 hours (+/- 15 minutes), 3 hours 
(+/- 15 minutes), 4 hours (+/- 15 minutes) and 24 hours (+/- 1 hour) post rucaparib dosing. Samples 
were also collected on day 1 of all subsequent cycles before PLX038 dosing.
There were 9 patients enrolled with sufficient PK data for inclusion in this analysis. Sparse 
sampling of rucaparib precluded a full-time course of concentration data needed to calculate most 
PK parameters. However, pre-dose (trough) concentrations at steady state (C1D8 and beyond) 
were analyzed by dose and compared to literature. While no proper statistical comparisons could 
be made, it appears rucaparib trough concentrations in this study were reasonably consistent with 
prior data (Figure 6).
Figure 6. Comparison of Steady-State Troughs (Pre-dose) of 300 mg or 400 mg Rucaparib given 
Orally Twice Daily.
The total plasma concentrations of SN38 and its UGT1A1-catalyzed metabolite, SN38-G, were 
measured in all evaluable patients (Figure 7). PLX038 was designed to prolong the half-life in 
humans (expected 120 hr [2]), and the observed half-life was consistent with this expected value. 
There were nanomolar levels of SN38, indicating minimal ex vivo release of SN38 from PLX038. 
The median metabolite: parent ratio of SN38-G to SN38 was 0.29, similar to literature [3]. There 
was insufficient PK data on subsequent cycles to assess accumulation on the q3wk schedule, or 
whether there was a drug interaction with rucaparib PO BID. However, both the patients at dose 
level 1A (patients #9 and #10) who developed neutropenic enterocolitis had elevated levels of 
SN38G compared to the other patients (Figure 8). We saw no genotype effect of UGT1A1*28 on 
SN38 or SN38-G exposures.


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36
Figure 7. Mean First Dose PLX038 (1 g/m2) Plasma Concentration vs Time Profile.
Figure 8. SN38-G AUC by Patient.
In summary, there were early signs of promising efficacy, but associated with intolerable GI 
toxicity at dose level 1, which prompted amendment of the protocol to reduce the dose of rucaparib 
and increase the gap between PLX038 and rucaparib. The first two patients treated with the 5-day 
gap (dose level 1A) developed drug-related neutropenic enterocolitis. Both rucaparib and PLX038 
are known to be associated with neutropenia and infection. While neutropenic sepsis leading to 
death is an expected AE with the class of TOP1 inhibitors (such as SN38), these events are 
considered as unexpected for PLX038 from a regulatory perspective as they had not previously 
been reported with PLX038. Thus, new risks from the combination have been uncovered during 
the course of the study, but given the patient population being studied – with resistant cancer and 
no other standard options, and the early responses observed, the combination might still be of 
0
1
2
3
4
5
6
7
8
9
10
2
3
4
5
6
7
8
9
10
AUC SN38G uM•h
Patient #


Abbreviated Title: PLX038 and Rucaparib
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37
potential benefit. The following considerations were discussed with drug manufacturers Clovis 
and Prolynx, and experts in the field with the goal of minimizing risk: 

The eligibility criteria were revised to include patients who have exhausted all approved 
standard options.

Individual patients will be observed for at least four weeks in the dose escalation phase 
before the next patient can be enrolled.

It is unlikely that an insufficient end-gap (gap between last dose of rucaparib and next dose 
of PLX038) contributed to the toxicities. Patient #9 had a 100-hour gap between last dose 
of rucaparib and cycle 2 PLX038 due to scheduling/logistical issues, doubled the 
prescribed 48-hour gap. Patient #10 had a 11-day gap since he stopped rucaparib early due 
to diarrhea and urinary infection. 

It is unlikely that excluding patients with heterozygous for UGT1A1*28 would help reduce 
toxicity. UGT1A1 is a hepatic enzyme that metabolizes SN38 to SN38-G. It is a 
polymorphic enzyme and UGT1A1*28, is often assessed for genotype. We found no 
genotype effect of UGT1A1*28 on SN38 or SN38-G exposures, and specifically patients 
9 and 10 were heterozygous for UGT1A1*28. The low SN38-G to SN38 ratio suggests 
sufficient UGT1A1 activity in patients treated thus far. The current standard of care does 
not require dose reduction of irinotecan in UGT1A1 heterozygotes, who are clinically 
much closer to homozygous wild type in terms of irinotecan safety than to homozygous 
mutant patients. Accordingly, the frequency of grade 3/4 neutropenia among patients 
treated with sacituzumab Govitecan, an antibody–drug conjugate with SN-38 payload were 
67% in patients homozygous for the UGT1A1 *28 allele and 46% each in patients 
heterozygous for the UGT1A1*28 and homozygous for the wild-type allele. 

Reducing the dose (calculated as g/m2) and capping the total dose of PLX038 may reduce 
the incidence of severe toxicities. Patient #9 received more than 3000 mg based on body 
surface area (Table 8). Other patients in the trial received doses of 2700 mg or lower 
including patient #10. In the phase I study of PLX038 monotherapy, the frequency and 
severity of diarrhea was higher among patients who received higher doses, especially at 
1300 mg/m2 or higher. 

Primary prophylactic G-CSF will decrease incidence of neutropenic events. Due to the 
potential for G-CSF to stimulate neutrophil precursors at the same time as 
myelosuppression from chemotherapy, it is recommended that G-CSF be administered 24 
hours after chemo administration. In addition, several studies have showed that use of G-
CSF on the same day as chemo may result in worse neutropenic outcomes [43]. While the 
timing of G-CSF is a concern given the extended tissue accumulation of PLX038, all 3 
patients who received G-CSF on study (patients #1, 7 and 8) have had appropriate increases 
in neutrophil counts. However, G-CSF will be administered at least 72-hours after PLX038 
given this theoretical risk. 
Table 8. Cumulative PLX038 cycle 1 dosing 
Patient
Cumulative PLX038 
dose in cycle 1, mg
1010001
2040
1010002
2171
1010003
2366


Abbreviated Title: PLX038 and Rucaparib
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38
1010004
1870
1010005
2150
1010006
2700
1010007
2510
1010008
2030
1010009
3110
1010010
2310
Based on the above considerations, the following dose levels are proposed going forward.
Dose level
PLX038 every 3 weeks, IV
Rucaparib, PO BID
Former dose level 1 
(completed)
1.3 g/m2
400 mg, days 3-19
Former dose level 1A
(completed)
1.3 g/m2
300mg, days 5-19
1B
580 mg/m2
300mg, days 6-19
2B
870 mg/m2
300mg, days 6-19
3B
1000 mg/m2
300mg, days 6-19
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
Eligibility Criteria
2.1.1
Inclusion Criteria 

Subjects with:
histologically confirmed solid tumors (Phase I)
OR
histologically or cytologically confirmed SCLC (Phase II) 
OR
histologically or cytologically confirmed extra-pulmonary small cell carcinomas 
(Phase II)

Age ≥18 years. Because no dosing or adverse event data are currently available on the use 
of PLX038 in combination with rucaparib in participants <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials.

Subjects must have progressed on or after standard first-line systemic chemotherapy and 
have no effective treatment options.

Participants must have disease that is not amenable to potentially curative resection.

Participants must have measurable disease per RECIST 1.1. See Section 6.3 for the 
evaluation of measurable disease.

Participants with asymptomatic brain metastases and treated brain metastases are eligible.

ECOG performance status ≤ 2 (Appendix A).


Abbreviated Title: PLX038 and Rucaparib
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39

Adequate hematological function defined by:
white blood cell (WBC) count ≥ 3 × 109/L, 
absolute neutrophil count (ANC) ≥ 1.5 ×109/L, 
platelet count ≥100 × 109/L, 
Hgb ≥9 g/ dL 

Adequate hepatic function defined by:
a total bilirubin level ≤ 1.5 × ULN, 
an AST level≤2.5×ULN, (≤ 5X ULN if liver metastasis)
an ALT level ≤2.5 ×ULN, (≤ 5X ULN if liver metastasis). 

Adequate renal function defined by:
Creatinine OR
Measured or calculated 
creatinine clearance 
(CrCl) (eGFR may also 
be used in place of 
CrCl) A
< 1.5x institution upper limit of normal OR
> 45 mL/min/1.73 m2 for participant with creatinine levels
> 1.5 X institutional ULN
A Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.

The effects of the study treatment on the developing human fetus are unknown; thus, 
women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry, for the 
duration of study treatment and up to 6 months after the last dose of the study drug (s). 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.

Subjects must be able to understand and willing to sign a written informed consent 
document.
2.1.2
Exclusion Criteria 

Participants who are receiving any other investigational agents.

Systemic anti-cancer treatment or major surgery within 2 weeks prior to enrollment.

Radiotherapy within 24 hours prior to enrollment.

Participants who require treatment with strong inhibitors or inducers of CYP3A or with 
UGT1A1 inhibitors during the planned period of investigational treatment with PLX038.

Participants with known Gilbert’s syndrome. 

Participants homozygous for the UGT1A1*28 variant allele with severely reduced 
UGT1A1 activity.


Abbreviated Title: PLX038 and Rucaparib
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40

Participants with known HIV, HCV, HBV status on antiviral drugs are excluded due to the 
absence of previous experience with concurrent use of antiviral medications and the 
investigational drug product to be evaluated in the current study and possible for adverse 
pharmacokinetic and/or pharmacodynamic interactions.

History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to PLX038 or rucaparib.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that may impair the participant’s tolerance of study 
treatments.

Pregnant women are excluded from this study because PEGSN38 and rucaparib potential 
for teratogenic or abortifacient effects are unknown. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with PEGSN38 and rucaparib, breastfeeding should be discontinued if the mother is treated 
with study drugs.
2.1.3
Recruitment Strategies
This study will be posted on the CCR website, www.clinicaltrials.gov and on NIH social media 
forums. Outside providers and colleagues may directly refer participants for screening into this 
study.
2.2
Screening Evaluation
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 

Email, written, in person or telephone communications with prospective subjects 

Review of existing medical records to include H&P, laboratory studies, etc. 

Review of existing MRI, x-ray, or CT images

Review of existing photographs or videos 

Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for study 
#01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research 
Program Clinical Protocols). Assessments performed at outside facilities or on another NIH 
protocol within the timeframes below may also be used to determine eligibility once a participant 
has signed the consent.
Within 14 days prior to treatment unless otherwise noted below:

Complete medical history and physical examination, including height, weight, vital signs, and 
ECOG performance status.


Abbreviated Title: PLX038 and Rucaparib
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41

EKG

Laboratory Evaluation
o
Hematological profile: CBC with differential and platelet count; 
o
Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total bilirubin, calcium, 
phosphorus, albumin, magnesium, uric acid;
o
 PT/PTT; 
o
Cholesterol (fasting);
o
Serum or urine pregnancy test for female participants of childbearing age (in the 
absence of prior hysterectomy) (7 days prior to treatment);
o
Urinalysis
o
Blood or buccal test for defining of UGT1A1 status by polymerase chain reaction 
(PCR) (any time prior to enrollment, outside test results are acceptable)

CT/MRI of chest, abdomen and pelvis;

Brain MRI (if clinically indicated);

Tumor evaluation / tumor measurements;

Histologic or cytologic confirmation from any certified laboratory (at any time point prior to 
enrollment). If there is no available documentation, biopsy will be performed to confirm the 
diagnosis.
2.3
Participant Registration and Status Update Procedures
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
2.3.1
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Phase I
Subjects with solid tumors enrolled to PLX038 and rucaparib escalation 
dose levels. 
2
Phase IIA
Subjects with SCLC enrolled at the MTD of PLX038 and rucaparib 
after the MTD of PLX038 and rucaparib is established.
3
Phase IIB
Subjects with extra-pulmonary small cell carcinomas enrolled at the 
MTD of PLX038 and rucaparib after the MTD of PLX038 and 
rucaparib is established.


Abbreviated Title: PLX038 and Rucaparib
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42
Arms
Number
Name
Description
1
Arm 1
Escalating doses of PLX038 and rucaparib
2
Arm 2
MTD of PLX038 and rucaparib
Arm assignment
Subjects in cohort 1 will be directly assigned to Arm 1.
Subjects in cohorts 2 and 3 will be directly assigned to Arm 2. 
2.4
Baseline Evaluation
Tests done at screening do not need to be repeated on baseline if performed in designated time 
frame prior to start of study treatment.
Within 14 days prior to first dose:

CT/MRI of chest, abdomen and pelvis

Tumor evaluation / measurements

Optional tumor research biopsy

Baseline symptoms evaluation

Concomitant medication

Collection of available unstained slides or a block from previous biopsies/surgeries for 
research
3
STUDY IMPLEMENTATION
3.1
Study Design
This is an open label Phase I/II trial, accruing initially one cohort to determine maximum tolerated 
dose (MTD) of combined treatment of PLX038 and rucaparib (Phase I); and to examine safety and 
efficacy of the PLX038 in combination with rucaparib in the following cohorts (Phase IIA and 
IIB). 
Up to 3 dose levels of combined treatment of PLX038 and rucaparib will be tested in Phase I 
(Table 9) with up to 18 subjects enrolled in addition to the 8 participants treated prior to 
amendment version 03/19/2021. Once an MTD of combined treatment of PLX038 and rucaparib 
has been determined, up to 35 subjects may be evaluated at MTD in the Phase II cohorts, inclusive 
of those participants treated at the MTD during the Phase I if they are eligible for the phase II 
evaluation.
Participants will receive treatment in cycles consisting of 21 (+7) days. 
Administration of PLX038 will be every 3 weeks by IV infusion starting on day 1 of cycle 1. 
Granulocyte-colony stimulating factors (G-CSF) should not be used within at least 24 hours of 
PLX038 administration. Outside of this restriction window, G-CSF may be administered as 
clinically indicated.


Abbreviated Title: PLX038 and Rucaparib
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43
Rucaparib will be administered on days 6 to 19 of a 21-day cycle starting at 300 mg PO BID. 
Treatment with PLX038 and rucaparib will continue until participant meets off treatment criteria 
(Section 3.7.1). 
Granulocyte-colony stimulating factors (G-CSF) will be given prophylactically in each cycle to 
prevent/treat neutropenia (for both phase 1 and phase 2). G-CSF will be administered at least 72-
hours after PLX038 in each cycle, with at least 14 days elapsing until the next planned 
chemotherapy dose. 
Optional biopsies may be performed at: baseline, on day 4 or 6 of Cycle 1 (prior to rucaparib 
dosing) and between days 7 and 14 of Cycle 1. 
Participants may be admitted for cycle 1 as there are PK studies planned to be performed. 
3.1.1
Dose Limiting Toxicity 
The DLT period is one cycle, 21 days. 
The following events will be considered DLTs if deemed drug-related (CTCAE v5.0): 

Grade 3 or 4 neutropenia complicated by fever ≥ 38.5°C (i.e. febrile neutropenia) and/or 
documented infection; 

Grade 4 neutropenia that does not resolve within 7 days

Grade 4 thrombocytopenia or grade 3 thrombocytopenia complicated with hemorrhage; 

Grade 4 anemia that does not resolve within 7 days despite optimal therapy; 

Inability to begin subsequent treatment course within 21 days of the scheduled date, due to 
study drug toxicity; 

Any grade 3 non-hematologic toxicity with the following exceptions
o
fatigue/asthenia lasting less than 2 weeks in duration
o
mucositis in subjects who have not received optimal therapy for mucositis
o
vomiting or diarrhea lasting less than 72 hours whether treated with an optimal anti-
emetic or anti-diarrheal regimen or not
o
alkaline phosphatase changes
3.1.2
Phase I Cohort
Dose escalation will follow the classical ‘3+3’ trial design by Fibonacci sequence with dose levels 
defined in Table 9. 
Starting dose level is Dose level 1B.
If none of the first three participants in a Dose level group experiences a dose-limiting toxicity 
during the DLT period, another three participants will be treated at the next highest dose level. 
However, if one of the first three participants experiences a dose-limiting toxicity during DLT 
period, three more participants will be treated at the same dose level. Dose escalation continues 
until the final dose level meets safety criteria (< 2 DLTs in 6 participants during DLT period) or 
at least two participants among a Dose level group of three to six participants experience dose-
limiting toxicities.


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Note: If there are ≥2 DLTs in the Dose level 1B, we will consider amending the study with new 
dose levels.
Table 9. Dosing schedule of PEGSN38 and rucaparib.
Dose level
PLX038 every 3 weeks, IV
Rucaparib, PO BID
Former dose level 1 
(completed)
1.3 g/m2
400 mg, days 3-19
Former dose level 1A
(completed)
1.3 g/m2
300mg, days 5-19
1B
580 mg/m2
300mg, days 6-19
2B
870 mg/m2
300mg, days 6-19
3B
1000 mg/m2
300mg, days 6-19
PLX038 dose will be capped at 2000 mg total dose. 
G-CSF will be administered at least 72-hours after PLX038 in each cycle.
The MTD is the dose level at which no more than 1 of 6 participants experience DLT during the 
DLT evaluation period, and the dose below that at which at least 2 (of 6) participants have DLT 
as a result of the drug. 
Every subject in each dose level group of the safety run-in will be observed for at least 4 weeks 
after first dose of PLX038 before the subsequent subject can be treated.
Subjects who do not complete the DLT observation period for reasons other than a DLT will be 
replaced and not included in the DLT evaluation.
Intra-participant PLX038 and rucaparib dose escalation or de-escalation are not permitted for 
subjects enrolled in the Phase I during the DLT finding period.
In case of DLT definitely attributed to one of the study drugs, participant will be taken off this 
drug and per PI discretion may continue treatment with the other drug alone.
Participant will be eligible for the DLT evaluation if at least ≥85 percent of rucaparib scheduled 
doses were taken within the DLT period. 
3.1.3
Phase II Cohorts
The safety and efficacy evaluation of the combination will continue during Phase II with the 
PLX038 and rucaparib MTD identified during phase I. 
We will initially enroll 16 evaluable subjects into cohort Phase IIA (inclusive of those participants 
with SCLC treated at the MTD during the safety run-in). If 2 or more of the first 16 subjects have 
clinical benefit, then accrual would continue to a total of 25 subjects. If less than 2 subjects have 
clinical benefit, enrollment into this cohort will be closed.
Simultaneously with enrollment of participants into cohort Phase IIA, up to 10 participants with 
extrapulmonary small cell cancers may be enrolled into cohort Phase IIB. CBR of these 
participants will not be included in the primary statistical analysis and will be described in an 
exploratory manner.
Enrollment into phase II part of the study can commence after DLT period of 6th subject of 
respective Dose level group is complete. 


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3.2
Study Stopping Rules
For safety reasons, enrollment will be temporarily halted until an expedited safety report is sent to 
and reviewed by the FDA and the SAE has been evaluated by the investigators for grade 5 toxicity 
attributable to treatment regimen occurring within 30 days of receiving investigational agents.
The stopping rule has been met with two patients having grade 5 events at dose level 1A, but will 
be applicable to future subjects who enroll. 
3.3
Drug Administration 
3.3.1
PLX038
PLX038 will be administered as a 1-hour (-10 minutes / +30 minutes) IV infusion on Day 1 of 
each cycle (21 days). 
PLX038 vials (220 mg/vial) should be brought to room temperature before use. However, the final 
diluted product should ideally be used as soon as possible. 
Vital signs will be collected within 1 hour before PLX038 infusions, at least once during the 
infusions, and within 30 minutes after the completion of the infusion.
To calculate the dosage, height measured at screening and weight measured at day 1 of current 
cycle will be used.
3.3.2
Rucaparib
Rucaparib will be given orally at designated dose twice a day on days 6 to 19 of every 21-day 
cycle. There should be a minimum 5 day window between PLX038 and rucaparib. 
Rucaparib should be taken at approximately the same times each day. Doses should be taken within 
2 hours of the scheduled time. 
In case of a missed dose (more than 2 hours late) or vomiting after taking rucaparib, participants 
will be instructed not to make up the missed dose.
Missing of 15% of the doses for any given cycle is allowed. 
Participants will be recommended to have 8 mg of ondansetron taken with small meal or snack to 
prevent nausea and vomiting approximately 30 minutes prior to each dose of rucaparib. 
Participants will complete and return Participant’s Diary (Appendix B).
3.4
Dose Delay or Modifications
In case of toxicity as defined below definitely attributed to one of the study drugs, participant will 
be taken off this drug and per PI discretion may continue treatment with another drug only.
For participants who are on combination therapy and benefiting from treatment, since we don’t 
know which agent is driving the response (i.e. either of the drugs alone or the combination), in the 
event that one drug is causing toxicities and has to be discontinued, it is reasonable to continue the 
other drug to see if the participant might benefit from it.
3.4.1
Phase I during evaluation period
See Section 3.1.2.


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3.4.2
Phase I after DLT evaluation period and Phase II
When, at the beginning of a treatment cycle, treatment delay related to PLX038 is indicated, 
treatment with rucaparib must be delayed too. There should be a minimum 48-hour window 
between PLX038 and rucaparib. 
If, in the opinion of the investigator, a toxicity is considered to be due solely to one drug, the dose 
of another drug does not require modification.
The dose of PLX038 and rucaparib may be reduced for toxicity using the following guidelines 
depending on the toxicities (and drug deemed to be responsible for toxicity) observed. 
Table 10: Dose reductions for rucaparib and PLX038
Rucaparib dose modifications (mg BID)
Dose level
100%
First dose reduction 
Second dose reduction
1B
300
200
 NA (participant will be taken off 
rucaparib treatment)
2B
300
200
NA (participant will be taken off 
rucaparib treatment)
3B
300
200
NA (participant will be taken off 
rucaparib treatment)
PLX038 dose modifications (mg/m2)
Dose level
100%
First dose reduction 
Second dose reduction
1B 
580
300
 NA (participant will be taken off 
PLX038 treatment)
2B
870
580
300
3B
1000
870
580
3.4.2.1
PLX038 toxicity management 
Grades 1 and 2 do not need dose adjustments
For grades 3 and 4, dose should be interrupted for up to 21 days. If resolved to Grade 2 or less, 
reduced Dose (see Table 10) will be used during next treatment cycle. If not resolved during 21 
days, participant will be taken off PLX038 treatment. Note: grade 3 nausea which resolves to grade 
1 within 7 days with appropriate supportive care and grade 3/4 lymphopenia do not need dose 
adjustments.
3.4.2.2
Rucaparib toxicity management
Grades 1 and 2 do not need dose adjustments
For grades 3 and 4, dose should be interrupted for up to 21 days. If resolved to Grade 2 or less, 
reduced Dose (see Table 10) will be used during next treatment cycle. If not resolved during 21 


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days, participant will be taken off PLX038 treatment. Note: grade 3 nausea which resolves to grade 
1 within 7 days with appropriate supportive care and grade 3/4 lymphopenia do not need dose 
adjustments.


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3.5
Study Calendar
C1
Procedure
Screening1
Baseline/
C1D11
C1D4
C1D6
C1D7
C1D8
C1D10
All Subsequent 
Cycles
Day 1 1
(Cycle=21+7 
days2)
30 
Days 
Safety 
FU11,13
Long 
Term 
FU12
PLX0382
X
X
Rucaparib3
X
X
Medical History
X
Height
X
Histologic confirmation of 
disease 
X
UGT1A1 testing 
X
EKG
X
Physical exam, weight and 
ECOG
X
X
X
Vital Signs
X
X4
X
CBC w/differential, platelets 
X
X14
 X
X
Cholesterol 
X
 X16
PT/PTT
X
Biochemical profile5
X
X
X
Radiologic Evaluation
X
X
X6
X
Brain MRI if clinically 
indicated
X


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C1
Procedure
Screening1
Baseline/
C1D11
C1D4
C1D6
C1D7
C1D8
C1D10
All Subsequent 
Cycles
Day 1 1
(Cycle=21+7 
days2)
30 
Days 
Safety 
FU11,13
Long 
Term 
FU12
Tumor evaluation / tumor 
measurements6
X
X
X
X
Urinalysis
X
Serum or urine pregnancy 
test
X1
X
Concomitant medications
X
X
Adverse event evaluation
X
X
Baseline symptoms 
evaluation
X
Tumor biopsy7
X
X
(day 4 or day 6)
X
 (between day 7-14)
Research blood for PLX038 
level8
X
X
X
Research blood for rucaparib 
level9
X
X
Research blood for Immune 
Subset Analysis17
X
X
X
Research blood for germline 
DNA
X
Research blood for PBMC 
PARylation and gH2AX18
X
X
X
X
Research blood for 
Circulating tumor DNA19
X
X


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C1
Procedure
Screening1
Baseline/
C1D11
C1D4
C1D6
C1D7
C1D8
C1D10
All Subsequent 
Cycles
Day 1 1
(Cycle=21+7 
days2)
30 
Days 
Safety 
FU11,13
Long 
Term 
FU12
Research blood for PLX038 
coagulation studies20
X
X
Collection of archival tumor 
samples for research15
X
Collection of hair follicles10
X
X
X
X
Phone call or e-mail for 
survival every 6 month
X
1.
Baseline and C1D1 evaluations do not need to be repeated if performed at screening or baseline in designated time frame. All evaluations 
will be done within 14 days before treatment initiation on Day 1 of Cycle 1(except for pregnancy test which should be performed within 7 
days). If treatment does not start within 28 days after enrollment, screening evaluations will be repeated. For all subsequent cycles, all 
evaluations are to be done within 7 days of cycle treatment initiation. 
2.
PLX038 via IV infusion on Day 1 of each cycle. Note: A cycle may vary in length (21 (+ 7) days) due to logistical reasons. PLX038 will be 
administered as a 1 hour (-10 minutes / +30 minutes) IV infusion.
3.
PO, BID on days 6-19 of every 21 days cycle. If cycle length varies, note that approximately 5 days must elapse between last dose of 
PLX038 and rucaparib.
4.
Vital signs will be collected within 1 hour before PLX038 infusions, at least once during the infusions, and within 30 minutes after the 
completion of the infusion.
5.
Biochemical Profile: electrolytes, BUN, creatinine, AST, ALT, total bilirubin, calcium, phosphorus, albumin, magnesium, uric acid. 
6.
CT/MRI of chest, abdomen and pelvis at screening/baseline and every 9 (+/-1) weeks after start of study therapy. If participant is taken off 
treatment for reason other than disease progression, imaging will continue during follow-up until disease progression.
7.
Optional tumor biopsies may be performed at baseline, on day 4 or 6 of Cycle 1 (prior to rucaparib dosing) and between days 7 and 14 of 
Cycle 1. 
8.
Cycle 1 day 1: before PLX038 infusion, end of infusion (EOI) (+5 minutes), 2 (+/- 15 minutes) hours, 4 (+/- 15 minutes) hours and 24 (+/- 
30 minutes) hours post EOI; cycle 1 day 6: just before starting rucaparib, cycle 2 day 1: before PLX038 infusion.
9.
Cycle 1 day 8 (optional): before rucaparib, 2 hours (+/- 15 minutes), 3 hours (+/- 15 minutes), 4 hours (+/- 15 minutes) and 24 hours (+/- 1 
hour) post rucaparib dosing. Samples will also be collected on day 1 of all subsequent cycles before PLX038 dosing.


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10. Collected pre-treatments on C1D1, C1D6 and C1D7 (24 hours after rucaparib dosing) and C2D1 before PLX038 infusion. To minimize 
participant discomfort, if good quality hair follicles are not collected at baseline (C1D1) or at the second collection (C1D6), no further hair 
collection will be done.
11. Follow up visit is planned to be performed at 30 (+/- 7 days) after treatment discontinuation to evaluate participant’s safety. 
12. After safety FU visit, subjects will be followed every 6 months (± 1 month) for survival by phone call or e-mail. NOTE: if participant is 
taken off treatment for reason other than disease progression, we will continue to invite participant every 9 (+/-1) weeks for imaging 
studies. Outside scans are acceptable.
13. If subjects are not willing to come to NIH for FU visits, they will be contacted by phone call or e-mail for adverse events (refer to 6.1 for 
AE collection).
14. Sample will be collected on C1D10 +/- 3 days.
15. Collection of available unstained slides or a block from previous biopsies/surgeries for research will be done within 14 days per 2.4.
16. Cholesterol will be monitored at least once at the C3D1 or C4D1 timepoint or earlier in the treatment regimen.
17. Immune Subset Analysis research blood will be collected at PLX038 Pre-treatment on C1D1, C1D7 (24 hours after rucaparib) and PLX038 
pre-treatment C2D1 per 5.3.5.
18. PBMC PARylation and gH2AX research blood will be collected at C1D1 (before PLX038), C1D6 (prior to rucaparib), C1D7 (24 hours 
after rucaparib), C2D1 (before PLX038). Blood sample does not need to be collected if hair sample is not collected.
19. Circulating tumor DNA research blood will be collected at PLX038 pre-treatment on C1D1, C2D1 and at disease progression.
20. PLX038 coagulation assay blood will be collection C1D1 before PLX038, C1D1 2 hours post PLX038 EOI and C2D1 before PLX038.


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3.6
Cost and Compensation
3.6.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they are 
not covered by insurance company. Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center.  
3.6.2
Compensation
N/A
3.6.3
Reimbursement 
This study offers subject reimbursement or payment for travel, lodging and/or meals while 
participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of the expenses. Some of the costs may be paid 
directly by the NIH and some may be reimbursed to the subject. Someone will work with subjects 
to provide more information.
3.7
Criteria for Removal from Protocol Therapy and Off Study Criteria
Prior to removal from study, efforts must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.7.1
Criteria for Removal from Protocol Therapy

Progressive disease 

Excessive toxicity attributed to both drugs (see sections 3.1.2 and 3.4)

PI discretion

Positive pregnancy test

PLX038 and rucaparib become unavailable
3.7.2
Off -Study Criteria

Death

Participant request to be withdrawn from study

PI discretion

Lost to follow up

PI decision to end the study
3.7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:


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
The site will attempt to contact the participant and reschedule the missed visits and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (telephone calls and if necessary, an IRB 
approved certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record 
or study file. 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/MEASURES
All routine and appropriate supportive care (including blood products) will be provided during this 
study, as clinically indicated, and in accordance with the standard of care practices. Clinical 
judgment should be utilized in the treatment of any AE experienced by the participant.
4.1
Prohibited Medications
4.1.1
Strong inducers or inhibitors of CYP3A4 and UGT1A1 inhibitors
Strong inducers or inhibitors of CYP3A4 and drugs that inhibit UGT1A1 should not be 
administered while on study treatment. UGT1A1 inhibitors include indinavir, atazanavir, nilotinib, 
and sorafenib (as well as certain herbal extracts). Additional guidance can be found in the 
following 
link: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-
drug-interactions-table-substrates-inhibitors-and-inducers#table3-2.
4.2
Required Medication
4.2.1
G-CSF 
Granulocyte-colony stimulating factors (G-CSF) are required to be administered prophylactically 
for all participants to prevent/treat neutropenia. G-CSF will be administered at least 72-hours after 
the dose of PLX038 in each cycle, with at least 14 days elapsing until the next planned 
chemotherapy dose.. 
4.3
Recommended Medication 
Participants will be recommended to take 8 mg of ondansetron with a small meal or snack to 
prevent nausea and vomiting approximately 30 minutes prior to each dose of rucaparib. 
5
CORRELATIVES STUDIES FOR RESERACH
5.1
Biospecimen Collection
A description of correlative studies including a brief statement of rationale and processing 
information is made below.


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Test/assay
Sample volume 
(approx.)
Type of tubea
Collection timepoint
Location of specimen 
Peripheral blood 
PLX038 Pharmacokinetic 
Analysis
5 mL
6 mL Purple (LVV) 
tube 
1) C1D1 
obefore PLX038
oEOI (+5 minutes)
o2 hours post EOI (+/- 15 min)
o4 hours post EOI (+/- 15 min)
o24 hours post EOI (+/- 30 min)
2) C1D6 (before rucaparib)
3) C2D1 (before PLX038)
Rucaparib 
Pharmacokinetic Analysis
5 mL
6 mL Purple (LVV) 
tube
1) C1D8 (optional)
obefore rucaparib
o2 hours post dosing (+/- 15 min)
o3 hours post dosing (+/- 15 min)
o4 hours post dosing (+/- 15 min)
o24 hours post dosing (+/- 60 
min)
2) C2D1 (before PLX038)
3) C3D1 (before PLX038)
4) C4D1 (before PLX038) 
Blood Processing 
Core (BPC)
Immune subset analysis
16 ml
8ml CPT citrate 
blue/black top tubes
1) C1D1 (before PLX038)
2) C1D7 (24 hours after rucaparib)
3) C2D1 (before PLX038)
DTB Clinical 
Translational Unit
Blood for germline DNA 
3ml 
3ml light blue citrate 
tube
1) Baseline 
Blood Processing 
Core (BPC)


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Test/assay
Sample volume 
(approx.)
Type of tubea
Collection timepoint
Location of specimen 
PBMC PARylation and 
gH2AXb
5ml 
6 mL Purple (LVV) 
tube 
1) C1D1 (before PLX038)
2) C1D6 (prior to rucaparib)
3) C1D7 (24 hours after rucaparib)
2) C2D1 (before PLX038)
Blood Processing 
Core (BPC), analysis 
to be performed by 
Suresh Kumar, DTB
Circulating tumor DNA 
10ml
cfDNA Streck tubes
1) C1D1(before PLX038)
2) C2D1(before PLX038)
4) At progression 
Blood Processing 
Core (BPC)
PLX038 Coagulation 
Studies
24 mL
3ml light blue citrate 
tube (8 tubes)
1) C1D1 
obefore PLX038
o2 hours post EOI (+/- 15 min)
2) C2D1 (before PLX038)
NIH DLM / Mayo 
Clinic
Tumor Biopsies 
γH2AX or other DNA 
damage markers by 
confocal 
microscopy/ELISA
PARylation by poly 
(ADP-ribose) assay 
SLFN11 by IHC and/or 
RNA 
Whole exome 
sequencing/RNAseq- 
bulk and or scRNA
Tumor sample
1) C1D1 
2) C1D4 or C1D6 (prior to 
rucaparib)
3) between C1D7 and C1D14
Frozen samples- DTB 
Clinical Translational 
Unit 
Formalin samples- 
Blood Processing 
Core (BPC), analysis 
to be performed by 
Suresh Kumar, DTB


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Test/assay
Sample volume 
(approx.)
Type of tubea
Collection timepoint
Location of specimen 
Archival tumor 
Whole exome 
sequencing/RNAseq
N/A (Archival tumor)
Baseline
Blood Processing 
Core (BPC), analysis 
to be performed by 
Suresh Kumar, DTB 
Hair follicles
yH2AX by confocal 
microscope/ELISA
N/A (Hair follicles)
1) C1D1 (before PLX038)
2) C1D6 (prior to rucaparib)
3) C1D7 (24 hours after rucaparib)
4) C2D1 (before PLX038)
Christophe Redon, 
DTB
a.
Please note that tubes and media may be substituted based on availability with the permission of the PI or laboratory investigator.
b.
Blood sample does not need to be collected if hair sample is not collected.


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5.2
Collection of Samples
5.2.1
Blood
Blood samples for PK will be collected at time points indicated in the Study Calendar 3.5. PK 
blood samples will be sent and processed by the Blood Processing Core (BPC). Non-PK blood 
samples will be sent to and processed by the DTB Clinical Translational Unit. 
5.2.2
Tumor samples
All possible attempts will be made to acquire archival pathologic tissue (i.e. original slides or 
paraffin blocks) or fresh frozen tumor (where available) for purpose of molecular studies. If a 
tumor block is not available, at least 20 unstained slides may be collected. 
Three optional tumor biopsies may be performed at time points indicated in Study Calendar 3.5. 
Frozen tumor samples will be procured by the DTB Clinical Translational Unit. Tissue for formalin 
fixation will be sent to the Laboratory of Pathology. Formalin-fixed samples will be analyzed for 
disease first, leftover will be used for research. Germline DNA will be collected for accurate 
culling of somatic variants from the tumor sample. 
5.2.3
Hair follicles
Hair follicles will be collected at time points indicated in the Study Calendar 3.5. Upon delivery 
in Dr. Redon lab, hairs will be fixed with paraformaldehyde and analyzed under a dissection 
microscope to select those containing a full intact follicle and sheath.
5.3
Correlative Studies for Research 
5.3.1
Pharmacokinetic analysis
Blood samples for the determination of PLX038 and rucaparib plasma trough levels will be 
obtained from participating participants at time points indicated in Study Calendar 3.5. 
Bioanalytical measurements will be conducted by the Clinical Pharmacology Program (CPP).
Blood samples for the determination of Rucaparib will be collected in room temperature lavender-
top (EDTA) tubes. 
The PLX038 collection tubes will also be lavender-top, but be pre-chilled and contain 1M citrate 
buffer with 0.1% Pluronic F68, pH4.5 in a 1:10 ratio with the volume of blood drawn. Tubes can 
be prechilled by completely immersing blood collection tube in bag of ice. After draw, gently 
invert the tube 3-5 times and immediately immerse the tube into the ice. Specimen must be 
processed within 1 hour of draw.
Page Figg lab for sample pick up at 102-11964.
5.3.2
The formation of γH2AX foci
γH2AX, the phosphorylated form of histone H2A histone family member X (H2AX) at serine 139, 
is a marker of DNA double-strand breaks. The formation of γH2AX foci of will be evaluated on 
plucked hair follicles and tumor by ELISA/confocal microscope. Plucked hairs and tumor will be 
fluorescently stained for γ-H2AX. 
5.3.3
PARP inhibition
PARP inhibition will be evaluated in pharmacodynamic studies by means of a functional assay 
(Mesoscale Discovery) involving the analysis of poly(ADP-ribose) (PAR) formation from 


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peripheral-blood mononuclear cells and tumor-tissue cell lysates, all normalized to the amount of 
PARP1 protein present.
5.3.4
SLFN11
Expression of the gene SLFN11 has been found to correlate with the activity of topoisomerase 
inhibitors in studies using the National Cancer Institute cell line panel (NCI60) and the Cancer 
Cell Line Encyclopedia (CCLE) [44, 45]. SLFN11 expression predicted sensitivity to DNA 
damaging chemotherapy including Top1 and Top2 inhibitors, alkylating agents, platinum 
derivatives, DNA synthesis and PARP inhibitors [44-46]. In experiments using cells with 
endogenously high and low SLFN11 expression and siRNA- and Crispr-mediated silencing, 
SLFN11 was found to be causative in determining cell cycle arrest and cell death in response to 
DNA damaging agents in cancer cells [46]. Data from the CCLE, the NCI60 and The Cancer 
Genome Atlas (TCGA) indicate a broad range of SLFN11 expression in lung cancers, raising the 
possibility that high SLFN11 expression might enrich for tumors that are more likely to respond 
to DNA damaging chemotherapy; conversely low SLFN11 expression may predict tumors that are 
likely resistant. 
SLFN11 is frequently inactivated in cancer cell lines and has been shown to sensitize cancer cells 
to anticancer drugs. In particular, elevated SLFN11 expression is associated with sensitivity to 
DNA-damaging agents which concurrently promote replication fork stalling and cell cycle 
checkpoint activation, and induce replication stress [47]. 
SLFN11 is highly expressed in SCLC as compared with other histologies [23]. In contrast, 
SLFN11 expression is low to nearly absent in lung squamous cell carcinoma and adenocarcinoma 
[48]. SLFN11 expression has a bimodal distribution in SCLC and may provide meaningful 
stratification as a predictive biomarker in clinical studies of SCLC. SLFN11 gene expression by 
RNA-Seq is concordant with SLFN11 protein expression by quantitative western blot. 
SCLC cells with high SLFN11 expression are more sensitive to DNA-damaging chemotherapy, 
and SLFN11 inactivation confers resistance to these agents [23]. Participants with SLFN11-
positive tumors treated with a combination of temozolomide and veliparib had a significantly 
prolonged PFS and OS compared with participants with SLFN11-negative tumors. Consistent with 
its role in determining chemosensitivity, SLFN11 expression is higher in tumors from SCLC 
participants who respond to DNA-damaging therapy versus those who do not and is higher in 
tumors from treatment-naive SCLC participants than in recurrent/relapsed SCLC [48]. Recent 
studies have shown that SLFN11 suppression by epigenetic silencing could be causal to acquired 
resistance to DNA-damaging chemotherapy in SCLC [48-50]. 
Based on the above considerations, we hypothesize that relapsed SCLC tumors with high SLFN11 
expression would be sensitive to PARP inhibitors and camptothecins.
Pre-treatment SLFN11 expression in tumor samples will be assessed (IHC and RNA sequence 
(Section 5.3.8)) to assess in an exploratory manner, the potentially role of SLFN11 as a predictor 
of response to PLX038 plus rucaparib.
5.3.5
Immune Subset Analysis 
Peripheral blood will be drawn into two 8ml BD Vacutainer Cell Preparation Tubes (CPT) with 
Sodium Citrate per 3.5 and 5.2.


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Depending on viable PBMC number, the following immune subsets will be assessed using 
multiparameter flow cytometry including but not necessarily limited to CD8+ T-cells, 
CD4+Foxp3- T-cells, Tregs, monocyte subsets, MDSC subsets. Assessment will include 
functional markers, i.e. PD-1, Tim-3, CTLA-4, PD-L1, HLA-DR and/or CD40. 
5.3.6
Circulating Tumor DNA 
Circulating tumor DNA is a promising biomarker that is being investigated in multiple tumor 
types. Changes in the levels of circulating tumor DNA can be used to monitor disease course, 
treatment responses, and recurrences. 
5.3.7
Interference of PLX038 with coagulation assays
On 20C0013 to date, after PLX038 infusion, 100% of patient who had post-infusions PTT checked, 
had new prolonged PTTs. Extensive evaluation in one patient showed that that the PTT 
prolongation was assay-specific and therefore did not representative of a true coagulation defect. 
Specifically, there was prolongation of the PTT using an assay with rabbit cephalin phospholipid 
with micronized silica activator but not with other PTT assays, suggesting in vitro assay 
interference but not a true in vivo coagulation defect such as an acquired clotting factor inhibitor. 
This has great significance for acutely ill patients with cancer receiving this drug, since 
interventions to treat an in vivo “inhibitor” that is a laboratory artifact would result in extended 
hospitalizations and unwarranted treatments with potentially toxic agents. A similar pattern has 
been described of a few other pegylated agents [51-54]. 
We hypothesize that PLX038 will interfere with PTT assays that use the micronized silica or 
colloidal silica dispersion activators, but not with other PTT assays, including those using kaolin, 
polyphenolic, or colloidal silica activators, based on the pattern described for a small few other 
pegylated agents and the mechanism of coagulation activation in these various assays [51-54]. We 
hypothesize that the remainder of the coagulation assays will be unaffected. We also hypothesize 
that the degree of interference will relate to the time of sampling post-dose administration, with 
the in vivo trough drug level showing less impact
Pre- and post-PLX038 infusion samples will be drawn to perform coagulation assays, including 
PT, PTT, thrombin time, reptilase time, fibrinogen, and lupus anticoagulant, using two different 
instrument analyzers and various reagents. In vitro studies using normal donor plasma will further 
investigate the interference. Normal donor samples will be spiked with varying concentrations of 
PLX038, PEG alone and SN-38. The resulting samples will be analyzed with coagulation assays 
shown in Table 11. 
Testing will be completed at NIH Department of Laboratory Medicine and Mayo Clinic 
Laboratories.
Table 11. Coagulation Assays
Test
Instrument
Assay
Location of 
testing
Stago
STA Neoplastine CI Plus 10
NIH
PT/INR
IL
RecombiPlasTin 2g
MAYO
PTT
Stago
STA-PTT Automate 5
NIH


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Test
Instrument
Assay
Location of 
testing
STA-C.K. Prest 5
NIH
STA-Cephascreen 4
NIH
STA-Cephascreen 10
NIH
STA-STACLOT dRVV Screen 2
NIH
STA-STACLOT dRVV Screen 5
NIH
STA-STACLOT dRVV Confirm
NIH
PTT-LA Screen
NIH
Staclot LA
NIH
Precision BioLogic CRYOcheck LA/LA sure
NIH
HemosIL Synth ASil
MAYO
HemosIL SynthAFax
MAYO
IL
HemosIL APTT-SP
MAYO
Stago
STA Thrombin 2 
NIH
Thrombin Time
IL
HemosIL Thrombin Time
MAYO
Stago
STA-Reptilase
NIH
Reptilase time
IL
Reptilase time
MAYO
Stago
STA Fibrinogen 5 
NIH
Fibrinogen C
MAYO
Fibrinogen
IL
Q.F.A. Thrombin
MAYO
Stago = Diagnostica Stago STA-R Evolution Analyzer. IL = Instrumentation Laboratory ACL Top 
700Samples for Genetic/Genomic Analysis
5.3.8
SLFN11 Expression
SLFN11 expression will be assessed by RNA sequencing and or IHC.
5.3.9
RNAseq and Whole Exome Sequencing 
In order to address the exploratory goal of characterizing predictive biomarkers of response, 
genomic analysis including but not limited to RNAseq and whole exome sequencing of tumor 
tissue may be performed.
5.3.10 Management of Results
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the American 
College of Medical Genetics and Genomics recommendations for the return of incidental findings 
that is current at the time of primary analysis. (A list of current guidelines is maintained on the 
CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists. 
Subjects will be contacted at that time with a request to provide a sample to be sent to a CLIA 
certified laboratory.
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 Disposition
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 may include 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. 
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. 


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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 DTB Clinical Translational Unit
Contact the DTB Clinical Translational Unit by email ( 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 DTB Clinical Translational Unit 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. 
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.


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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.
5.4.4
Procedures for Storage of Tissue Specimens in the Laboratory of Pathology
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
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.
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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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. 
6
DATA COLLECTION AND EVALUATION 
6.1
Data Collection
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.


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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. 
6.2
Data Sharing Plans
6.2.1
Human Data Sharing Plan
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.
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.


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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.


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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.


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For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response 
when Confirmation is 
Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not evaluated
No
PR
>4 wks. Confirmation**
SD
Non-CR/Non-
PD/not evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
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.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated


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Non-Target Lesions
New Lesions
Overall Response
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised
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.
6.4
Toxicity Criteria
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).
7
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN
7.1
Definitions
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP Office of Compliance and Training / IRB Reporting
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to 
be reported per these policies.


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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&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
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.
7.4
NIH Required Data and Safety Monitoring Plan
7.4.1
Principal Investigator/Research Team 
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.
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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8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
Definitions
8.1.1
Adverse Event 
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)).
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:

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.
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).
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.


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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)
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
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:


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
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.
8.3
Reporting of Serious Adverse Events
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.
8.4
Waiver of Expedited Reporting to CCR
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)).
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators
Reporting will be per the collaborative agreements.
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.
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND
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.
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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9
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.   
10 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 


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and rucaparib in previously treated participants with small cell lung cancer and extra-
pulmonary 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).
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.
10.4 Statistical Analyses
10.4.1 General Approach
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; 


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
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
11 COLLABORATIVE AGREEMENT
11.1 Cooperative Research and Development Agreement (CRADA)
The CRADA for this protocol has been executed between NCI, NIH and ProLynx (CRADA 
#03286). 
11.2 Clinical Trial Agreement (CTA)
The CTA for this protocol has been executed between NCI, NIH and Clovis Oncology (CTA 
#01141-19).
12  HUMAN SUBJECTS PROTECTIONS 
12.1 Rationale for Subject Selection
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.
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.
12.3 Evaluation of Benefits and Risks/Discomforts 
12.3.1 Benefits
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)
TEAEs
Serious TEAEs
System Organ Class  
Preferred Terma
All Grades 
n (%)
CTCAE
≥ Grade 3
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


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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 
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. 
b Combined 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 (ATHENA-
MONO) is 23 March 2022. 
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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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; 
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-338-
087 (ATHENA-MONO) is 23 March 2022. 
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%). 
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 
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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
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.
Risk related to possibility that information may be released
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.
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 


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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.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS
13.1 Study Discontinuation and Closure
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:


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
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).
13.2 Quality Assurance and Quality Control
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 Council 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.
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.
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. 


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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.
14 PHARMACEUTICAL INFORMATION
14.1 PLX038 (IND 145310)
14.1.1 Source
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. 


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14.1.4 Stability and Storage 
PLX038 lyophilized product should be stored at 2-8o 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.
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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Abbreviated Title: PLX038 and Rucaparib
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16 APPENDICES
16.1 Appendix A - Performance Status Criteria
ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
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 Medication Diary
Cycle___________________   Participant’s ID ___________________
INSTRUCTIONS TO THE PATIENT:
1.
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.
Record the date, the number of tablets that you took, and when you took them.
6.
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. 
7.
If you have any comments or notice any side effects, please record them in the comments column.
8.
Please bring this form and your bottles (even it is empty) when you come for your clinic visits.
# of Oral Rucaparib 
Tablets taken
(every 12 hours)
Day
Date
AM
PM
Comments (side effects or missed doses)
1
Do not take rucaparib.
2
Do not take rucaparib.
3
Do not take rucaparib.
4
Do not take rucaparib.
5
Do not take rucaparib.
6
7
8
9
10
11
12


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# of Oral Rucaparib 
Tablets taken
(every 12 hours)
Day
Date
AM
PM
Comments (side effects or missed doses)
13
14
15
16
17
18
19
20
Do not take rucaparib.
21
Do not take rucaparib.
Participant’s signature: ___________________________________________________