Clinical trial NCT03030417
Conditions: Solid Tumors Lymphoma
Keywords: Topoisomerase I Inhibitor Epithelial-Mesenchymal Transition Pharmacodynamics DNA Damage Pharmacokinetics
Sponsor: National Cancer Institute (NCI)
Start date: 2017-02-27; Completion date: 2023-10-12
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

The new drug LMP744 (NSC 706744) damages deoxyribonucleic acid (DNA). This causes cell death. Researchers want to see if it can treat certain kinds of cancer. They want to understand how the drug works and how it affects the body.

Objective:

To test the safety of LMP744 and find out the dose of the drug that can be safely given to humans.

Eligibility:

Adults at least 18 years old who have metastatic solid tumors or lymphoma, which have progressed after other treatment.

Design:

Participants will be screened with:

* Vital signs taken
* Blood and urine tests
* Heart tests
* Scans or ultrasound

Some participants will have a tumor sample taken 2 times. A small piece of tumor is removed by a small needle. A scan or ultrasound will guide the process.

The study will be done in 28-day cycles.

Each cycle, participants will get the study drug in a vein for 60 minutes once a day for 5 days.

For day 1 of cycle 1, participants will be admitted to the clinic and have blood and urine taken several times.

At the beginning of each cycle, participants will have a clinic visit and repeat some screening tests. They will also do this twice in the middle of cycle 1 and once in the middle of cycle 2.

After participants stop taking the study drug, they will be followed for 30 days. They may give blood samples. They will be contacted by phone to see how they are doing....

Detailed description:
Background:

* Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) with improved characteristics over their predecessors. Indenoisoquinolines have better chemical stability, producing stable deoxyribonucleic acid (DNA)-top1 cleavage complexes, and exhibit a preference for unique DNA cleavage sites, compared with their camptothecin counterparts.
* They have demonstrated activity against camptothecin-resistant cell lines and produce DNA-protein crosslinks, which are resistant to reversal. They also show less or no resistance to cells overexpressing the ATP-binding cassette (ABC) transporters, ATP-binding cassette super-family G member 2 (ABCG2), and multidrug resistance (MDR-1).

Primary Objectives:

-To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 (NSC 706744) administered intravenously (IV) daily for 5 days every day (QD) x 5) schedule in patients with refractory solid tumors and lymphomas.

Secondary Objectives:

-Characterize the pharmacokinetic (PK) profile of LMP744.

Exploratory Objectives:

* Evaluate the effect of LMP744 on markers of DNA damage phosphorylated H2AX (γH2AX), phosphorylated Nijmegen breakage syndrome 1 (pNbs1), pATR, excision repair cross-complementation group 1 (ERCC1), RAD51 recombinase (RAD51), Topo1cc, topoisomerase 1 (Top1), Schlafen family member 11 (SLFN11) and epithelial-mesenchymal transition (EMT) in circulating tumor cells (CTCs) and pre- and post- treatment tumor biopsies in patients at the expansion cohort.
* Assess preliminary antitumor activity of LMP744.
* Examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated with response or resistance to treatment

Eligibility:

-Adult patients must have histologically documented, relapsed solid tumors which have progressed after one line of therapy, or lymphoma which has progressed after initial therapy and without potentially curative options, or patient refuses potentially curative therapy.

Study Design:

* Cycle 1 and subsequent cycles: Patients will receive LMP744 administered IV QD over 1 hour on days 1-5 followed by 23 days without drug (28-day cycle).
* Pharmacokinetic (PK) and pharmacodynamic (PD) samples will be collected. Tumor biopsies will be mandatory during the expansion phase.

LMP744 will be administered IV over 1 hour on days 1-5 of each 28-day cycle.

Blood samples for PK analyses will be collected at the following timepoints in cycle 1 only:

Day 1, prior to drug administration, 2 minutes (+/- 2 minutes) before end of infusion, and at appropriate time points post infusion (15 minutes, 30 minutes, and 1, 2, 4, and 6 hours post infusion)

Day 2, 24-hour (hr) post day 1 start of infusion (prior to day 2 infusion), and 2 minutes (+/- 2 minutes) before the end of infusion

Day 3, 24 hr post day 2 start of infusion (prior to day 3 infusion), and 2 minutes (+/- 2 minutes) before end of infusion

Day 4, 24 hr post day 3 start of infusion (prior to day 4 infusion), and 2 minutes (+/- 2 minutes) before end of infusion

Day 5, 24 hr post day 4 start of infusion (prior to day 5 infusion), and 2 minutes (+/- 2 minutes) before end of infusion

Day 8, 72 hr post day 5 start of infusion Blood for circulating tumor cells (CTCs) (optional) will be collected at baseline, on day 3 of

Cycle 1 (within 2 to 4 hours after the start of LMP744 infusion), on day 1 of every subsequent cycle (prior to drug infusion), and at disease progression.

Tumor biopsies (mandatory in expansion phase) will be obtained at baseline and then on day 2 (1-4 hours after the LMP744 infusion) in cycle 1 only.

Arms: arm 1: LMP744 (NSC 706744) will be administered intravenous (IV) over 1 hour on days 1-5 of each 28-day cycle.
Interventions: intervention 1: LMP744 intervention 2: Ondansetron intervention 3: Olanzapine intervention 4: Lorazepam intervention 5: Diphenoxylate hydrocholoride (HCL) + Atropine Sulfate intervention 6: Loperamide intervention 7: Diphenhydramine intervention 8: Steroid intervention 9: Epinephrine
Intervention descriptions: intervention 1: Indenoisoquinolines, such as LMP744, are potent inhibitors of the enzyme topoisomerase I (Top1). Top1 is necessary for transcription, replication, recombination, and the repair of double-strand deoxyribonucleic acid (DNA) breaks. It relaxes the supercoiled DNA by introducing a single-strand break, generating a free strand that rotates around the Top1-bound DNA complex. In the absence of external triggers, Top1-DNA cleavage complexes are generally short lived. Top1 inhibitors are potent anticancer agents because they stabilize the formation of the Top1-DNA cleavage complex in tumor cells, which induces DNA damage, delays DNA repair, and results in cell cycle arrest and apoptosis. LMP744 exhibited antitumor activity with lower toxicity than other agents in preclinical studies. Treatment of patients with LMP744 is expected to reduce tumor burden at doses that are well-tolerated. intervention 2: Anti-emetic for nausea or vomiting. intervention 3: Persistent nausea or vomiting. intervention 4: Persistent nausea or vomiting. intervention 5: Diphenoxylate hydrocholoride (HCL) 2.5 mg + Atropine Sulfate 0.025 mg/tablet for diarrhea. intervention 6: Antidiarrheal. 4mg by mouth (PO) after first unformed stool and 2mg PO every 2 hours as long as unformed stools continue. No more than 16mg during a 24-hour period. intervention 7: Diphenhydramine 50 mg intravenous (IV) for allergic reaction. intervention 8: For allergic reaction at discretion of principal investigator. intervention 9: For allergic reaction at discretion of principal investigator.

Protocol documents:
Prot_SAP_000.pdf: 
CC: 17-C-0045 
CTEP P10002 
1 
 
TITLE:   A Phase I Study of Indenoisoquinoline LMP744 in Adults With Relapsed Solid 
Tumors and Lymphomas  
 
Short Title: Phase I LMP744 
 
Coordinating Center: 
Developmental Therapeutics Clinic (NCIDTC) 
 
National Cancer Institute  
 
10 Center Drive 
 
Bethesda, MD 20892 
 
Principal Investigator: 
Alice P. Chen MDA-E 
Center Drive Bldg 31 Rm 3A44 
Bethesda, MD 20892 
Phone: (240) 781-3274; Fax: (240) 541-4515 
chenali@mail.nih.gov 
 
Participating Organizations:  University of Pittsburgh Cancer Institute  
 
Referral Contact:  
Murielle Hogu, RN, DCTD/NCIA,B,E 
 
 
Bldg 10/Rm 8D53  
Phone: (240) 858-3335 
 
 
Fax: (301) 402-4270 
murielle.hogu@nih.gov  
 
Statistician:  
Larry Rubinstein, PhD, BRB/DCTDE 
9609 Medical Center Dr, Room 5W106 
Phone: (240) 276-6026  
rubinsteinl@mail.nih.gov 
 
NCI-supplied Agent(s): 
LMP744 (NSC 706744) 
 
IND Sponsor: 
DCTD, NCI 
 
IND Number: 
131535 
 
ClinicalTrials.gov Identifier: 
NCT03030417 
 
Version Date: 
January 6, 2023  
 
 
Participating Site:  
University of Pittsburgh Medical Center: 
FWA #00006735 
 
IRB of Record: U Pittsburgh Medical Center  
3500 Fifth Avenue, Hieber Building,  
 
PI: Liza Villaruz, MD 
UPMC Cancer Pavilion 
5150 Centre Avenue, Room 564 
Pittsburgh, PA 15232 


2 
 
Main Office, Suite 106 
Pittsburgh, PA 15213 
(412) 383-1480 
irb@pitt.edu 
IRB IORG # 0000196 
 
Pharmacy: Brian M. Miller, PharmD 
Investigational Drug Service, Hillman Cancer 
Center 
Ground Floor, AG40.3, 5115 Centre Avenue 
Pittsburgh, PA 15232 
Phone: 412-623-3381 
Fax: 412-623-0337 
Pager: 412-958-1586 
millerbm2@upmc.edu 
 
Phone: 412-648-6577  
Fax: 412-648-6579 
villaruzl@upmc.org 
 
 
 
 
Roles: Aobtains information by intervening or interacting with living individuals for research 
purposes; Bobtains identifiable private information about living individuals; Cobtains the 
voluntary informed consent of individuals to be subjects; Dmakes decisions about subject 
eligibility; Estudies, interprets, or analyzes identifiable private information or data/specimens for 
research purposes 
 
 
 


3 
 
PRÉCIS 
 
Background:  
• Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) with 
improved characteristics over their predecessors.  Indenoisoquinolines have better chemical 
stability, producing stable DNA-top1 cleavage complexes, and exhibit a preference for 
unique DNA cleavage sites, compared with their camptothecin counterparts.  
• They have demonstrated activity against camptothecin-resistant cell lines and produce DNA-
protein crosslinks, which are resistant to reversal.  They also show less or no resistance to 
cells overexpressing the ATP-binding cassette (ABC) transporters, ABCG2, and multidrug 
resistance (MDR-1).  
Primary Objectives: 
• To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 
(NSC 706744) administered intravenously (IV) daily for 5 days (QD x 5) schedule in patients 
with refractory solid tumors and lymphomas. 
Secondary Objectives: 
• Characterize the pharmacokinetic (PK) profile of LMP744. 
Exploratory Objectives: 
• Evaluate the effect of LMP744 on markers of DNA damage (γH2AX, pNbs1, pATR, 
ERCC1, RAD51, Topo1cc, Top1, SLFN11) and epithelial-mesenchymal transition (EMT) in 
circulating tumor cells (CTCs) and pre- and post- treatment tumor biopsies in patients at the 
expansion cohort. 
• Assess preliminary antitumor activity of LMP744. 
• Examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated 
with response or resistance to treatment. 
Eligibility: 
• Adult patients must have histologically documented, relapsed solid tumors which have 
progressed after one line of therapy, or lymphoma which has progressed after initial therapy 
and without potentially curative options, or patient refuses potentially curative therapy. 
Study Design: 
• Cycle 1 and subsequent cycles: Patients will receive LMP744 administered IV QD over 1 
hour on days 1–5 followed by 23 days without drug (28-day cycle).  
• PK and PD samples will be collected.  Tumor biopsies will be mandatory during the 
expansion phase. 
 
 
 
 
 
 
 
 


4 
 
SCHEMA 
 
 
 
 
LMP744 will be administered IV over 1 hour on days 1-5 of each 28-day cycle  
 
Blood samples for PK analyses will be collected at the following timepoints in cycle 1 only:  
• Day 1, prior to drug administration, 2 minutes (+/- 2 minutes) before end of infusion, and 
at appropriate time points post infusion (15 minutes, 30 minutes, and 1, 2, 4, and 6 hours 
post infusion) 
• Day 2, 24 hr post day 1 start of infusion (prior to day 2 infusion), and 2 minutes (+/- 2 
minutes) before the end of infusion 
• Day 3, 24 hr post day 2 start of infusion (prior to day 3 infusion), and 2 minutes (+/- 2 
minutes) before end of infusion 
• Day 4, 24 hr post day 3 start of infusion (prior to day 4 infusion), and 2 minutes (+/- 2 
minutes) before end of infusion 
• Day 5, 24 hr post day 4 start of infusion (prior to day 5 infusion), and 2 minutes (+/- 2 
minutes) before end of infusion 
• Day 8, 72 hr post day 5 start of infusion  
 
Blood for circulating tumor cells (CTCs) (optional) will be collected at baseline, on day 3 of 
cycle 1 (within 2 to 4 hours after the start of LMP744 infusion), on day 1 of every subsequent 
cycle (prior to drug infusion), and at disease progression.  
 
Tumor biopsies (mandatory in expansion phase) will be obtained at baseline and then on day 2 
(1-4 hours after the LMP744 infusion) in cycle 1 only. 
 
 
 
 
 


5 
 
 
Dose Escalation 
 
Dose Levels  
Dose Level 
LMP744 mg/m2/day x 5 days every 28-days (IV) 
Level-1 
3 
Level 1 
6 
Level 2 
12 
Level 3 
24 
Level 4 
48 
Level 5 
96 
Level 6 
190 
Level 7 
260 
Level 8 
360 
Level 9 
500 
* Doses are stated as exact dose in units (mg/m2) 
 
 
 
 
 
 


6 
 
TABLE OF CONTENTS 
 
PRÉCIS ............................................................................................................................................3 
SCHEMA .........................................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................6 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives...................................................................................................8 
1.2 
Secondary Objectives...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Preclinical Activity ..................................................................................................9 
2.2 
Preclinical Pharmacokinetics .................................................................................10 
2.3 
Preclinical toxicology ............................................................................................13 
2.4 
Correlative Studies Background ............................................................................14 
2.5 
Rationale ................................................................................................................15 
3. 
PATIENT SELECTION ....................................................................................................16 
3.1 
Eligibility Criteria ..................................................................................................16 
3.2 
Exclusion Criteria ..................................................................................................17 
3.3 
Inclusion of Women and Minorities ......................................................................18 
3.4 
Eligibility Screening Evaluation ............................................................................18 
4. 
REGISTRATION PROCEDURES ...................................................................................19 
4.1 
Investigator and Research Associate Registration with CTEP ..............................19 
4.2 
Patient Registration ................................................................................................20 
5. 
TREATMENT PLAN ........................................................................................................21 
5.1 
Indenoisoquinoline Administration .......................................................................22 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................24 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................25 
5.4 
Duration of Therapy ...............................................................................................27 
5.5 
Duration of Follow Up ...........................................................................................27 
5.6 
Criteria for Removal from Study ...........................................................................27 
6. 
DELAYS/DOSE MODIFICATIONS ................................................................................27 
6.1 
Drug-related toxicity ..............................................................................................28 
6.2 
Intra-patient Dose Escalation and De-escalation ...................................................30 
6.3 
Dose and Cycle delays ...........................................................................................30 
6.4 
Reporting and Exclusions ......................................................................................30 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................30 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................31 
7.2 
Adverse Event Characteristics ...............................................................................33 
7.3 
Expedited Adverse Event Reporting ......................................................................33 


7 
 
7.4 
Multicenter Guidelines for Expedited Adverse Event Reporting .................. Error! 
Bookmark not defined. 
7.5 
Routine Adverse Event Reporting ......................... Error! Bookmark not defined. 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................36 
8.1 
Agent Ordering and Agent Accountability ............................................................37 
8.2 
Investigator Brochure for LMP744 ........................................................................38 
8.3 
Useful Links and Contacts .....................................................................................38 
9. 
CORRELATIVE STUDIES ..............................................................................................39 
9.1 
Pharmacokinetics ...................................................................................................39 
9.2 
Pharmacodynamics ................................................................................................40 
10. 
STUDY CALENDAR .......................................................................................................44 
11. 
MEASUREMENT OF EFFECT........................................................................................46 
11.1 
Antitumor Effect ....................................................................................................46 
11.2 
Solid Tumors ..........................................................................................................46 
11.3 
Lymphomas............................................................................................................52 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................54 
12.1 
Data Reporting .......................................................................................................54 
12.2 
Data Safety and Monitoring Plan ...........................................................................54 
12.3 
Multicenter Guidelines...........................................................................................55 
12.4 
CTEP Multicenter Guidelines ................................................................................56 
12.5 
Collaborative Agreements Language .....................................................................57 
13. 
STATISTICAL CONSIDERATIONS...............................................................................57 
13.1 
Study Design/Endpoints.........................................................................................57 
13.2 
Sample Size/Accrual Rate ......................................................................................57 
13.3 
Analysis of Secondary Endpoints ..........................................................................58 
14. 
HUMAN SUBJECTS PROTECTION ..............................................................................58 
14.1 
Rationale for Subject Selection ..............................................................................58 
14.2 
Justification for Exclusions ....................................................................................59 
14.3 
Participation of Children ........................................................................................59 
14.4 
Evaluation of Benefits and Risks/Discomforts ......................................................59 
14.5 
Consent and Assent Process and Documentation ..................................................59 
REFERENCES ..............................................................................................................................61 
Appendix A: Performance Status criteria ......................................................................................63 
Appendix B: CTEP Multicenter Guidelines ..................................................................................64 
Appendix C: PD/PK Collection Worksheets at the NCI ...............................................................66 
Appendix D: Procedure for Samples for Pharmacodynamic Studies Collected at Participating 


8 
 
Sites ....................................................................................................................................71 


CC: 17-C-0045 
CTEP P10002 
9 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
• To establish the safety, tolerability and the maximum tolerated dose (MTD) of LMP744 
(NSC 706744) administered intravenously (IV) daily for 5 days (QD x 5) schedule in 
patients with refractory solid tumors and lymphomas. 
 
1.2 
Secondary Objectives 
 
• Characterize the pharmacokinetic (PK) profile of LMP744 
1.3 
Exploratory Objectives 
 
• Evaluate the effect of LMP744 on markers of DNA damage (γH2AX, pNbs1, pATR, 
ERCC1, RAD51, Topo1cc, Top1, SLFN11) and epithelial-mesenchymal transition 
(EMT) in circulating tumor cells (CTCs) and pre- and post- treatment tumor biopsies in 
patients at the expansion cohort 
• To assess preliminary anti-tumor activity of LMP744  
 
 
2. BACKGROUND 
 
Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase I (Top1), an enzyme 
necessary for transcription, replication, recombination, and the repair of double-strand DNA 
breaks(1).  Top1 relaxes the supercoiled DNA by introducing a single-strand break, generating a 
free strand that rotates around the Top1-bound DNA complex.  Once DNA is relaxed, Top1 re-
ligates the break.  In the absence of external triggers, these Top1-DNA cleavage complexes are 
generally short lived and re-ligation is favored over cleavage(2). Top1 inhibitors are potent 
anticancer agents because they stabilize the formation of the cleavage complex, which induces 
replication transcription-mediated DNA damage, delays DNA repair, and results in cell cycle 
arrest and apoptosis. 
 
Despite the potency and specificity of the Top1-inhibitor class, the therapeutic profile of 
camptothecin and its derivatives (such as topotecan and SN-38), has been offset by a number of 
shortcomings; including chemical instability induced by the fast conversion of the α-
hydroxylactone in the E-ring to a carboxylate exhibiting high affinity for human serum albumin, 
fast reversibility of the trapped DNA-Top1 cleavage complex following drug removal, drug 
resistance mediated by ATP-binding cassette (ABC) transporters, such as ABCG2 (MXR or 
BCRP) and multidrug resistance (MDR-1 or ABCB1), and dose limiting toxicities (DLTs).   
 
Indenoisoquinolines were identified as potential Top1 inhibitors following a COMPARE 
analysis of the NCI’s in vitro anticancer drug discovery screen (3).  They have improved 
characteristics over their camptothecin predecessors, with better chemical stability (lack of the 
labile hydroxylactone E-ring) producing stable DNA breaks that are resistant to reversal of the 


10 
 
trapped DNA-Top1 cleavage complex (2, 4).  Additionally, they trap the cleavage complex at 
different DNA sequences than camptothecins, which may result in differential activity within the 
cell (2).  Finally, indenoisoquinolines have been shown to have activity against camptothecin-
resistant cell lines and mouse models (4).  
 
 
Two of the indenoisoquinolines developed through the DCTD Developmental Therapeutics 
Program, LMP400 and LMP776, have already undergone clinical evaluation at the NCI in 
patients with refractory solid tumors: the first-in-human phase I study of LMP400 and LMP776 
(10-C-0056, NCT01051635) evaluated an intravenous (iv) daily for 5 days (QDx5) schedule, and 
the phase I study of LMP400 (13-C-0080, NCT01794104) evaluated a weekly iv (days 1, 8, 15 
q28-day cycle) schedule.  For LMP400, an MTD of 60 mg/m2/day was established for the daily 
regimen and an MTD of 90 mg/m2 for the weekly regimen.  Although no objective responses 
were observed on either schedule, 4 patients had best response of stable disease.  The TopI 
response to drug showed target engagement in a subset of tumor biopsies, and the 
pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation 
compared to topotecan.  Dose-dependent decreases in total CTCs were measured in 7 patients, 
and formation of γH2AX-positive foci in CTCs and hair follicles were measured following 
treatment.  The principal toxicity of both schedules was myelosuppression; no significant 
gastrointestinal problems were observed.   
 
Patients continue to be accrued to the LMP776 arm of 10-C-0056; 6 of the 32 LMP776 patients 
have had stable disease SD with an average of 109.3 days duration (range 56 to 249 days).  
 
The structurally related indenoisoquinoline LMP744 (NSC 706744), developed in parallel with 
LMP776 and LMP400, has also undergone extensive preclinical evaluation.  LMP744 exhibited 
antitumor activity in rats without the dose-limiting neutropenia that occurred with similar doses 
of LMP400 (unpublished data) and has shown marked clinical activity in dogs with lymphoma; 
LMP744 induced greater and more sustained reduction in tumor burden in these animals 
compared to either LMP400 or LMP776 (unpublished data).   
 
2.1 
Preclinical Activity 
 
In in vitro hollow fiber activity studies at the NCI, the mean graph midpoint (MGM) for 
LMP744 growth inhibition of all human cancer cell lines in the NCI 60 cell line screen was 15.5 
µM (5).  In in vitro studies, LMP744 inhibited TopI to a similar extent as 1 µM camptothecin, 
and although camptothecin and LMP744 trap Top1 at similar sites on DNA, LMP744 was more 
potent(6).  LMP744 also inhibited Top1 in CEM human leukemia cells, and time course studies 
demonstrated that Top1-DNA cleavage complexes reversed more slowly after drug removal than 
those produced by camptothecin.  Notably, human CEM/C2 leukemia cells resistant to CPT were 
sensitive to LMP744 at 0.1 µM (4). 
 
LMP744 also had modest activity in human tumor xenograft models.  In the HCT-116/H1 colon 
tumor model, the highest non-lethal dose of LMP744, 33.5 mg/kg/dose (100 mg/m2/dose) IV on 
a qdx 5 schedule, caused a mean tumor growth delay of 53% (%T/C=38).  In the A375 
melanoma model, an LMP744 dose of 22.4 mg/kg/dose (67.2 mg/m2/dose) IV on a qdx 5 
schedule resulted in a mean growth delay of 34% (%T/C=38).  Topotecan (NSC 609099) was 


11 
 
more active than NSC706744 at a dose of 4 mg/kg IP using the same schedule. 
 
Efficacy in a Comparative Oncology Trial with Canine Lymphoma (Protocol COTC007b) 
Antitumor activity was also observed with LMP744 in a canine clinical trial of 21 dogs with 
lymphoma.  LMP744 was administered via 1 h IV infusion qdx5 in 28-day cycles.  The MTD 
was determined to be 5 mg/kg (100 mg/m2).  The waterfall plot below (Figure 1) shows the best 
overall response per RECIST criteria for each dog; the majority (16/21) had partial responses 
(tumor shrinkage > 30%) and 5/21 had stable disease.  Responses were observed at all dose 
levels, with a single complete response occurring in Dose Level 2 (2.5 mg/kg or 50 mg/m2).  
There was no correlation between dose and extent of response.  Another 12 dogs were treated at 
the study MTD in a planned expansion cohort.  The overall response rate (PR or better) for all 
animals treated at this dose (6 escalation + 12 expansion) was 78%.  The overall response rate 
across all dose levels was 80%.  However, the responses were not durable, and most dogs had 
progressive disease in cycle 1 (manuscript in preparation). 
 
 
 
Figure 1: Canine COTC007b Trial best overall response (RECIST criteria) to increasing doses 
of LMP744. 
 
2.2 
Preclinical Pharmacokinetics 
The pharmacokinetics of LMP744 following IV administration were evaluated in IND-directed 
studies in rats and beagle dogs and in a canine comparative oncology trial.  Plasma drug 
concentrations were determined using a validated LC-MS/MS method.  Non-compartmental PK 
parameters were calculated for each animal (Phoenix WinNonlin, Version 6.3). 
 
Pharmacokinetics in Rats 
Rats (3 rats/sex/dose group) were given LMP744 at doses in the table below as a one-hour IV 
infusion on days 1-5.  Blood samples were drawn on Day 1 for plasma drug level determination 
immediately prior to the end of the infusion, 5, 15, 30, 60, 120 min and 4, 8, and 24 hrs post-
infusion; then pre-dose and just prior to the end of infusion on Day 5.  On Day 1, mean Cmax (M 
+ F) was 39.0, 234, and 259 ng/mL at 1, 5, and 10 mg/kg/day, respectively.  The mean AUClast 
was 110 hr*ng/mL, 399 hr*ng/mL, and 530 hr*ng/mL for the above doses, respectively.  The 
PR 


12 
 
resulting plasma clearance was similar across dose levels (7.0-13.7 L/hr/kg in males and females 
combined.  On day 1, systemic exposure, as represented by Cmax and AUC generally increased 
in a dose-proportional manner between 1 and 5 mg/kg, but was not dose-proportional between 5 
and 10 mg/kg.  Mean Cmax did not change significantly between Days 1 and 5, suggesting that 
LMP744 did not accumulate over the 5-day dosing period.  There was no difference in systemic 
exposure between males and females. 
 
 
Pharmacokinetics in Dogs 
LMP744 was given to dogs (8 dogs/sex/dose group) as a one-hour infusion qdx5 at the doses in 
the table above.  Blood samples were drawn from each dog for plasma drug level determinations 
just prior to the end of the infusion, and at 30, 120, 360, 480 min and 24 hr post-infusion on Day 
1; then pre-dose and just prior to the end of infusion on Day 5.  
 
On Day 1, mean Cmax (M + F) was 42.4, 230, and 294 ng/mL at 0.5, 2.5, and 5 mg/kg/day, 
respectively.  The T1/2 ranged from 4.96 to 18 hr and was shorter at the lowest dose.  This is 
likely a result of analytical sensitivity limiting plasma quantification to 8 hr post-infusion in the 
LMP744 PK Parameters in rats (IITRI Study 2330-013-001) 
Dose 
(mg/kg/day) 
Male 
or 
female* 
Cmax 
(ng/mL) 
AUClast 
(hr•ng/mL) 
AUCinf 
(hr•ng/mL) 
T1/2 
(hr) 
CL 
(L/hr/kg) 
Vz 
(L/kg) 
1 
M Day 1 
47.4  ±  28.4 
109 ± 53.6 
146 ± 92.4 
10.8 ± 10.8 
9.7 ± 7.18 
86.8 ± 46.9 
M Day 5 
41** 
 
 
 
 
 
F Day 1 
30.6  ± 9.87 
111 ± 11.7 
137 ± 17.5 
11.6 ± 1.16 
7.39 ± 0.90 
123 ± 12.1 
F Day 5 
41.1 ±15 
 
 
 
 
 
5 
M Day 1 
221 ± 130 
431 ± 115 
713*** 
24.6*** 
7.01*** 
24.8*** 
M Day 5 
132 ± 57.9 
 
 
 
 
 
F Day 1 
246 ± 100 
367 ± 73.3 
549 ± 91.0 
23.9 ± 6.52 
9.27 ± 1.55 
315 ± 78.8 
F Day 5 
113 ± 87.8 
 
 
 
 
 
10 
M Day 1 
252 ± 22.4 
518 ± 55.1 
730 ± 47.2 
19.0 ± 2.02 
13.7 ± 0.88 
378 ± 63.3 
M Day 5 
196 ± 8.83 
 
 
 
 
 
F Day 1 
265 ± 20.9 
541 ± 51.4 
821 ± 90.2 
22.3 ± 1.31 
12.3 ± 1.36 
394 ± 29.0 
F Day 5 
160 ± 66.2 
 
 
 
 
 
LMP744 PK parameters in dogs (IITRA Study  No. 2330-013-002) 
Dose 
(mg/kg/day) 
Male 
or 
female 
Cmax* 
(ng/mL) 
AUClast 
(hr*ng/mL) 
AUCinf 
(hr*ng/mL) 
T1/2 
(hr) 
CL 
(L/hr/kg) 
Vz 
(L/kg) 
0.5 
M Day 1 
44.5  ±  14.4 
122 ±  23.2 
139  ± 28.9 
6.39  ±  4.22 
3.73  ±  0.76 
31.0  ±  16.3 
M Day 5 
41.3  ±  8.00 
 
 
 
 
 
F Day 1 
40.3  ±  4.48 
88.3  ±18.7 
101  ± 20.0 
4.96  ±  3.41 
5.10  ±  0.87 
33.5  ±  15.4 
F Day 5 
41.4  ±  3.71 
 
 
 
 
 
2.5 
M Day 1 
284  ±  198 
579 ±  56.6 
712  ± 79.3 
14.5  ±  2.65 
3.55  ±  15.4 
73.9  ±  12.7 
M Day 5 
270  ±  21.7 
 
 
 
 
 
F Day 1 
177  ±  20.3 
446  ± 52.3 
575  ± 91.5 
15.0  ±  3.32 
4.44  ±  0.78 
94.5  ±  13.9 
F Day 5 
156  ±  33.6 
 
 
 
 
 
5 
M Day 1 
412  ±  62.9 
868 ±  79.2 
1157±  144 
18.0  ±  3.84 
4.37  ±  0.56 
112  ±  16.3 
M Day 5 
363  ±  56.4 
 
 
 
 
 
F Day 1 
177  ±  45.2 
798 ±  62.2 
996  ±  112 
14.4  ±  3.70 
5.07  ±  0.60 
104  ±  18.8 
F Day 5 
308  ±  96.4 
 
 
 
 
 
*Tmax was 1 hr (the end of infusion) for all dose groups.  Only 1 time point (end of infusion) was sampled on Day 5. 
 ** N=2; ***Lambda z and dependent parameters determinable for only 1 of 3 rats 


13 
 
low dose group vs. 24 hr in the other groups.  The mean (M+F) AUCinf was 120 hr*ng/mL, 
643 hr*ng/mL, and 1076 hr*ng/mL for the 0.5, 2.5, and 5 mg/kg/day groups, respectively.  Plasma 
clearance was relatively constant across dose levels (range 3.7 to 5.1 L/hr/kg) and the values were 
similar to those obtained in the pilot studies.  Systemic exposure on Day 1, as represented by 
Cmax and AUC, increased in an approximately proportional manner over the dose range studied.  
Mean Cmax (at end of infusion) did not change appreciably between Days 1 and 5, suggesting that 
LMP744 did not accumulate over the 5-day dosing period.  Systemic exposure tended to be 
slightly higher for male dogs compared with females (1.1 to1.6-fold for Cmax and 1.1-1.4-fold for 
AUCinf).  
Figure 2:  Plasma and tumor concentration-time plots from representative animals receiving 
LMP744 at the doses indicated (Study COTC007b). 
 
LMP744 was also evaluated in a multicenter comparative oncology clinical trial in dogs with 
lymphoma.  Drug (1.25, 2.5, 3.75, 5.0, and 6.25 mg/kg) was administered over 1 h IV daily x 5, 
in 28-day cycles.  Plasma samples were obtained for drug level determination during the infusion 
and for 24 hr after the infusion on days 1 and 5; levels of LMP744 were also determined in 
tumor biopsies obtained prior to treatment, at 2 and 6 hr after the start of the infusion on day 1, 
and at 24 hr after the last infusion.  The mean elimination half-life was 17 hr and the plasma 
clearance was 3.95 L/hr/kg, values similar to those observed in the IND-directed PK-toxicology 
study at comparable doses.  Non-compartmental analysis also suggested linear relationships 


14 
 
between plasma Cmax and dose and between AUC and dose.  LMP744 distributed extensively to 
tumor tissue and mean tumor concentrations were at least an order of magnitude higher than 
plasma concentrations in most animals at equivalent time points of 2, 6, and 120 hr (Figure 2).   
 
Levels of LMP744 also appeared to increase in tumor tissue over the 5-days of dosing, with 
levels at 120 hr (24 hours after the last dose) approximately 10-fold higher than levels measured 
at 2 and 6 hr on day 1. 
 
2.3 
Preclinical toxicology 
 
LMP744 was administered to Fischer rats and beagle dogs orally or as an intravenous infusion in 
pilot/range-finding studies using a single dose or multiple dose (daily x 5) schedule.  The data 
from these studies were used to select doses for IND-directed studies in which LMP744 was 
administered as a 1-hr infusion once daily for five days (the intended clinical route and 
schedule).   
 
An initial range-finding study in rats explored the toxicity of LMP744 administered as a single 
oral gavage or intravenous bolus dose.  Bone marrow toxicity was observed with both routes of 
administration.  Renal and injection site toxicity occurred only with the iv route.  The maximum 
tolerated dose (MTD) using the iv route was >100 mg/kg or >600 mg/m2; for the oral route, the 
MTD was between 500 and 750 mg/kg (3000 and 4500 mg/m2) due to lethality. 
 
A definitive study was conducted in rats.  Doses of 1, 5, or 10 mg/kg/day (6, 30, or 60 
mg/m2/day) LMP744 were given as a 1-hr infusion once daily for 5 consecutive days.  Bone 
marrow, thymic, and renal toxicity and pulmonary thrombi were observed.  Decreases in total 
WBC, neutrophils, and reticulocytes occurred in all LMP744 dose groups.  Thymic atrophy was 
noted in the high dose group.  Adverse effects in the kidney consisted of elevated BUN in the 
mid- and high-dose groups and minimal and/or mild microscopic renal tubular degeneration in 
all dose groups including vehicle control.  Minimal and/or mild tubular single cell necrosis was 
also noted in mid- and high-dose group males.  On the last day of the study (Day 19), BUN 
values were normal in all dose groups.  Tubular single cell necrosis was absent on Day 19, and 
tubular degeneration was present at a lower incidence and/or severity at the same time point.  
Tubular degeneration was not present in the vehicle control group on Day 19.  Pulmonary 
thrombosis occurred in all LMP744 dose groups on Days 6 and/or 19 and in one vehicle control 
animal on Day 19—incidence and severity were highest in the high dose group on Day 6.  The 
finding in the vehicle control animal suggests that the indwelling catheter contributed to the 
formation of pulmonary thrombi.  The MTD for the study was >10 mg/kg/day (>60 mg/m2/day).  
LMP744 peak plasma levels and AUCs on this study were 39 ng/mL to 259 ng/mL and 
110 hr∙ng/mL to 530 hr∙ng/mL, respectively, over the dose range studied.  
 
A single dose non-GLP toxicology study was conducted using LMP744 as a 1-hr iv infusion in 
dogs.  Lethality occurred at both doses on the study (35 and 50 mg/kg) (700 and 1000 mg/m2).  
Liver, gastrointestinal, bone marrow, renal, lung, injection site, and skin toxicity were observed.  
A subsequent study in dogs was conducted using doses of 5, 25, or 50 mg/kg given as a 15-min 
iv infusion.  A dose of 50 mg/kg was lethal.  The MTD on this study was between 5 and 25 
mg/kg (100 and 500 mg/m2) due to liver, renal, and bone marrow toxicity.  A third study was 


15 
 
conducted in dogs given LMP744 via a 1-hr infusion once daily for 5 days.  Bone marrow and 
GI toxicity occurred, but renal and hepatic toxicities were not observed.  The MTD for this study 
was 5 mg/kg/day (100 mg/m2/day).  Allergic reactions (erythema of the eyes, face, and legs) 
were observed in dogs on all of the above studies.  This schedule (daily x 5) and rate of 
administration (1-hr infusion) were used for the definitive toxicology study in dogs. 
 
A definitive toxicology study was conducted in which dogs were given a 1-hr infusion of 
LMP744 once daily for 5 consecutive days.  The no-observable adverse effect level (NOAEL) 
was 0.5 mg/kg/day (10 mg/m2/day).  The MTD was between 2.5 and 5 mg/kg/day (50 and 
100 mg/m2/day) based on irreversible bone marrow, bladder, and liver toxicity.  Dogs that 
received 5 mg/kg/day had facial swelling, a potential allergic reaction.  LMP744 also caused 
hematological toxicity at doses of 2.5 or 5 mg/kg/day (50 or 100 mg/m2/day).  Hematologic 
toxicity consisted of decreased total WBC, neutrophils, lymphocytes, eosinophils, and 
reticulocytes.  Decreased bone marrow hematopoiesis was noted microscopically in the 
5 mg/kg/day dose group.  Hepatic toxicity was observed in the 5 mg/kg/day dose group and was 
characterized by increased levels of ALP, fibrinogen, AST, ALT, GGT, and total bile acids.  Bile 
duct hyperplasia and inflammation of the portal tracts of the liver were noted microscopically in 
the same dose group.  Mononuclear cell inflammation suggestive of hemorrhagic cystitis was 
noted in the bladder of one female given 5 mg/kg/day.  
 
Based on the results of these nonclinical studies, the first-in-human dose (FHD) will be 
6 mg/m2/day administered as a 1-hr intravenous infusion once daily for 5 days.  This dose is 
approximately one-fifth the highest non-severe toxic dose (HNSTD; 5 mg/kg/day = 
30 mg/m2/day) in rats, the more sensitive of the two preclinical species tested.  Target organs of 
toxicity identified considering both species were bone marrow, kidney, liver, bladder, and lung.  
Allergic reactions (e.g., facial swelling and erythema) may also occur. 
 
2.4 
Correlative Studies Background 
 
2.4.1 γ-H2AX  
One of the earliest markers of DNA double-strand breaks is phosphorylation of histone 
H2AX, (γH2AX) (7-9).  γH2AX is phosphorylated at its C-terminus (serine 139 in 
humans) within minutes following DNA double-strand breaks and forms macromolecular 
foci, marking the chromatin domain around the broken chromosomal DNA ends, thus 
allowing the recruitment of repair factors(7, 8, 10-12).  Levels of γH2AX directly 
correlate with the amount of double-strand breaks per cell.  Hence γH2AX can be used as 
a dosimeter and biomarker for DNA double-strand breaks (13).   
 
In this study, drug-induced changes in γH2AX in circulating tumor cells and tumor 
biopsies will be measured by %NAP (representing the percent of nuclear area that is 
γH2AX-positive based on nuclear DAPI and γH2AX staining). γH2AX analysis will be 
complemented by the measurement of cleaved caspase-3 levels.  Caspase-3 cleavage and 
activation is a marker of apoptosis, and increased levels suggest that delayed repair of 
DNA double-strand breaks is resulting in tumor cell death.  In addition to apoptotic 
markers, tumor biopsies will be analyzed for autophagic activity based on expression of 
the autophagosomal marker LC-3. 


16 
 
 
2.4.2 Circulating tumor cells (CTCs) 
Recent progress in monitoring treatment responses of patients with breast cancer has 
provided evidence that a significant number of circulating tumor cells (CTCs) are present 
in peripheral blood, and these CTCs can be detected in a significant portion of patients 
with advanced disease.  Decreases in CTC levels were shown to predict disease-free and 
overall survival, independent of treatment, at the end of a treatment regimen (14-18).  
CTCs in the peripheral blood of cancer patients may potentially represent a compartment 
of solid tumor cells that allows more frequent PD assessment of molecular drug action 
than it is currently possible using tumor biopsy procedures.  CTCs will be isolated from 
whole blood samples collected at baseline and then throughout the study for assessment 
of DNA damage response markers such as γH2AX.  We will also evaluate whether we 
can measure changes in the number and phenotype (epithelial-mesenchymal transition) of 
CTCs in patients over time to explore any correlation with response to treatment or 
disease progression.  This analysis will be performed in Dr. Kinders’ lab with the 
ApoStream instrument, which uses antibody independent CTC isolation technology that 
can isolate viable CTCs from epithelial and nonepithelial cancers.   
 
2.4.3 Topoisomerase 1 
Recent preclinical and clinical data suggest that levels of top1 in pre-dose biopsies may 
serve as a potential predictor of response to top1 inhibitors (18, 19).  Results from the 
FOCUS (Fluorouracil, Oxaliplatin, CPT-11) clinical trial in patients with advanced 
colorectal cancer suggested a correlation between top1 levels and the efficacy of 
irinotecan-based chemotherapy; the overall survival benefit for patients with high levels 
of top1 (median benefit 5.3 months, hazard ratio 0.60) was substantially greater than for 
patients with moderate or low levels (median benefit 1.09, hazard ratio 0.92)(19). Further 
clinical studies and analyses are ongoing to confirm these results.  A validated 
immunoassay has been developed that could potentially provide a means of screening 
patients prior to treatment as well as monitoring patient response during treatment with 
top1 inhibitors.   
 
2.5 
Rationale 
 
Indenoisoquinolines possess structural improvements over camptothecin and its derivatives (6, 
20).  They have better chemical stability, produce stable DNA breaks that are resistant to the 
reversal of the trapped DNA-top1 cleavage complex (2, 4, 21), trap the cleavage complex at 
unique DNA sequences, possibly leading to differential activity within the cell (2), and have 
shown activity against camptothecin-resistant cell lines (4). Based on promising preclinical data, 
specifically in dogs with lymphoma, and data from studies of two related indenoisoquinolines, 
we are conducting this trial of LMP744 to evaluate its safety, pharmacokinetic, and 
pharmacodynamic profile in patients with refractory solid tumors. 


17 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically documented metastatic solid tumors which have 
progressed after one line of therapy, or lymphoma which has progressed after initial 
therapy and without potentially curative options, or patient refuses potentially 
curative therapy. 
 
3.1.2 Patients must have measurable or evaluable disease. 
 
3.1.3 Age ≥18 years.   
 
3.1.4 ECOG performance status ≤2 (see Appendix A). 
 
3.1.5 Life expectancy of greater than 3 months. 
 
3.1.6 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
within normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal (ULN) 
− 
serum creatinine 
≤1.5 × institutional ULN 
OR 
− 
creatinine clearance 
≥60 mL/min/1.73 m2 for patients with serum creatinine 
levels >1.5 × higher than institutional normal 
 
3.1.7 Anticoagulation with low-molecular-weight heparin (LMWH) or any direct oral 
anticoagulant (DOAC, e.g., rivaroxaban, apixaban, dabigatran, or edoxaban) will be 
permitted.  Patients receiving treatment with warfarin will be given the option to 
switch to LMWH or a DOAC. 
 


18 
 
3.1.8 Patients must have recovered to grade 1 or baseline from adverse events (22) and/or 
toxicity of prior chemotherapy or biologic therapy.  They must not have had 
chemotherapy, biologic therapy, or definitive radiotherapy within 4 weeks (6 weeks 
for nitrosoureas and mitomycin C) or 5 half-lives, whichever is shorter, prior to 
entering the study.  Palliative-intent radiotherapy (30 Gy or less) must be completed 
at least 2 weeks prior to start of treatment, and may not be to a lesion that is included 
as measurable disease.  Patients must be ≥2 weeks since any investigational agent 
administered as part of a Phase 0 study (where a sub-therapeutic dose of drug is 
administered) at the PI’s discretion, and should have recovered to grade 1 or baseline 
from any toxicities.  
 
3.1.9 Patients receiving denosumab or bisphosphonates for any cancer, or undergoing 
androgen deprivation therapy for prostate cancer, are eligible for this therapy.   
 
3.1.10 Prior therapy with topoisomerase I inhibitors is allowed. 
 
3.1.11 Patients with known HIV-positive status are eligible provided the following criteria 
are met: CD4 count >350/mm3, an undetectable viral load, and not receiving 
prophylaxis antibiotics.  Diagnostic HIV testing will not be performed during 
screening or throughout this study.   
 
3.1.12 The effects of LMP744 on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for 
the duration of study participation.  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.  Women and men treated or enrolled on this 
protocol must also agree to use adequate contraception prior to the study, for the 
duration of study participation, and 4 months after completion of LMP744 
administration. 
 
3.1.13 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.14 Willingness to provide blood and new tumor biopsy samples for research purposes if 
on the expansion phase of the study. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who are receiving any other investigational agents. 
 


19 
 
3.2.2 Patients with clinically significant illnesses which would compromise participation in 
the study, including, but not limited to active or uncontrolled infection, immune 
deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled 
hypertension, symptomatic congestive heart failure, unstable angina pectoris, 
myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements.  
 
3.2.3 Patients with known brain metastases or carcinomatous meningitis are excluded from 
this clinical trial, with the exception of patients whose brain metastatic disease status 
has remained stable for ≥ 1 month after treatment of the brain metastases.  Patients on 
anti-seizure medications or steroid therapy may be enrolled at the discretion of the 
Principal Investigator. 
 
3.2.4 Pregnant women are excluded from this study because LMP744 is an agent with the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the 
mother with LMP744, breastfeeding should be discontinued if the mother is treated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.  
 
3.4 
Eligibility Screening Evaluation 
 
3.4.1 History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, and ECOG performance score) will be 
conducted within 8 days prior to enrollment.   
 
3.4.2 Imaging Studies (Baseline): Every participant should have an evaluation of known 
sites of disease as part of the baseline evaluation.  All patients will be required to 
undergo a CT scan of the chest/abdomen/pelvis to evaluate sites of disease within 
28 days prior to enrollment.  MRI or CT scan with contrast of the brain, MRI liver, 
MRI for other disease sites, or bone scan may be done as clinically indicated.  When 
indicated, gadolinium contrast will be used for MRI scans and iodine-based contrast 
will be used for CT scans.  A PET scan will be done additionally to CT or MRI for 
lymphoma patients at baseline. 
 
3.4.3 Laboratory Evaluation: Laboratory data are to be obtained within 8 days prior to 
enrollment: 
• 
Hematological Profile: CBC with differential.  
• 
Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, BUN, 
bicarbonate, calcium, chloride, creatinine, glucose, phosphorus, total protein, 
SGOT (23), SGPT (10), TSH, sodium, GGT.  Uric acid and LDH levels will also 
be measured in patients with lymphoma only. 
• 
Urinalysis 


20 
 
• 
Coagulation Profile: PT, PTT, INR (on the expansion cohort) 
• 
Serum or urine pregnancy test for female participants of childbearing potential.  
 
3.4.4 Cardiac Evaluation:  
• 
EKG: to be conducted within 8 days prior to enrollment 
• 
ECHO: to be conducted within 28 days prior to enrollment 
 
4. REGISTRATION PROCEDURES 
 
4.1 Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (24) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 


21 
 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
For questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Patient Registration 
 
Authorized staff must register an eligible candidate with NCI Central Registration Office (25) 
and through the Theradex Interactive Web Response System (IWRS) within 24 hours after 
signing consent.  Access IWRS through https://iwrs.theradex.com under the “Patient” tab 
utilizing your CTEP-IAM Username and Password.  A registration Eligibility Checklist from 
the Web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed 
and sent via encrypted email to the NCI Central Registration Office (HOIS; 
ncicentralregistration-l@mail.nih.gov).  After confirmation of eligibility at the Central 
Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the 
patient on the protocol prior to the release of any investigational agents.  Verification of 
Registration will be forwarded electronically via e-mail.  Patient enrollment data entered in 
IWRS will automatically transfer to the NCI’s clinical data management system, Medidata 
Rave. 
 
Please note that it is very important for all registrars to acquire encrypted e-mail from NIH 
Help Desk, since the verification of registration includes patient’s information.   
 
Off Protocol Therapy and Off-Study Procedure: Authorized staff must notify the Central 
Registration Office (25) when a patient is taken off protocol therapy and when a patient is 
taken off-study.  The Participant Status Updates Form from the Web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to the NCI Central Registration Office (HOIS; ncicentralregistration-
l@mail.nih.gov).   
 
4.2.1 Interactive Web Response System (IWRS) 
 
Patient Enrollment will be facilitated using the Interactive Web Response System 
(IWRS).  IWRS is a web-based registration system available to users on a 24/7 basis.  On 
a successful registration, IWRS will assign a patient number and assign the treatment.  
Patient enrollment data entered by Registrars in IWRS will automatically transfer to the 
NCI’s clinical data management system, Medidata Rave.  IWRS will provide a printable 
confirmation of registration and treatment information.  Please print this confirmation for 
your records. 


22 
 
• 
Users must have a valid CTEP-IAM account (i.e., CTEP username and password) 
to access the IWRS system. 
• 
Users defined with the Registrar role will have the ability to register patients in 
the study. 
• 
Users defined with the Client Administrator role will have the ability to manage 
accrual limits, open and close treatment assignments as well as approve slot 
reservations, if applicable to the study. 
• 
For trials with slot reservation requirements, Registrars will have the ability to 
request to reserve a slot, which may require approval from users at the lead 
institution defined as a ‘Client Administrator’ for the study. 
 
5. TREATMENT PLAN 
 
This is a multicenter phase I trial evaluating the intravenous administration (IV) of LMP744 over 
1 hour on days 1-5 followed by 23 days without drug (28-day cycle, see Schema).  After cycle 1, 
the infusion may be administered over 1 hour +/- 10 minutes.  After cycle 2, the start of a new 
cycle may begin up to 3 days earlier than it would otherwise be scheduled or be delayed up to 1 
week to accommodate scheduling conflicts and other unexpected events.  LMP744 will be 
administered via central line.  If the patient has a central line (such as a port-a-cath or a tunneled 
Hickman catheter) at the time of enrollment, treatment will be administered via this route.  If the 
patient does not have one, a temporary central line (such as a PICC) will be placed and removed 
after the last treatment infusion of LMP744. 
 
Patient evaluations will be performed throughout the study as described below.  Baseline history, 
physical examination, pre-treatment tumor biopsy, laboratory evaluations, urinalysis, and EKG 
must be conducted within 8 days prior to start of protocol therapy.  If protocol therapy is started 
within 8 days of the screening evaluations (see Section 3.4), the screening evaluations may be 
used as baseline measurements.  If >8 days have passed since the screening evaluations, the 
medical history, physical examination, laboratory evaluations, urinalysis, and EKG must be 
repeated prior to starting protocol therapy.  Tumor imaging and baseline ECHO must be 
performed within 28 days prior to start of protocol therapy.  
 
History and physical examination will be done at baseline (within 8 days prior to start of protocol 
therapy), during week 2 of cycle 1, and at the start of every cycle thereafter (within 3 days prior 
to treatment).   
 
Labs (CBC with differential; serum chemistries) and urinalysis will be performed at baseline 
(within 8 days prior to start of protocol therapy), on D8 and D15 of cycle 1, on D1 and D15 of 
cycles 2 and 3, and then at the start of each cycle (up to 3 days before start of a new cycle).   
 
Blood and urine samples for correlative research studies will be collected as described in 
Section 9.  Tumor biopsies will be mandatory in the expansion phase.   
 
CT scans will be performed at baseline (within 28 days prior to start of protocol therapy), and 
repeat imaging scans will be performed every 2 cycles (every 3 cycles for patients on study for 
more than 1 year; every 4 cycles for patients on study more than 3 years).  For patients with 


23 
 
lymphoma, a PET scan will be done at baseline if clinically indicated, and repeated at restaging 
if clinically indicated or required for restaging purposes. 
 
CT-guided biopsies (mandatory for patients in the expansion phase) will be collected at baseline 
and on D2 of cycle 1 for research purposes. 
 
Baseline EKG (within 8 days prior to start of protocol therapy) and baseline ECHO (within 
28 days prior to start of protocol therapy) will be performed.  EKG and ECHO will be repeated 
before cycles 3 and 5 (up to 1 week prior to start of cycle), and as clinically indicated thereafter. 
 
5.1 
Indenoisoquinoline Administration 
 
Treatment may be administered in the outpatient service.  Patients must be monitored in clinic 
for allergic/hypersensitivity reactions for a minimum of 1 hour after receiving drug during cycle 
1 and as clinically indicated thereafter.  
 
5.1.1 Dose Levels 
 
Dose escalation in this study initially followed design 3 of the Simon accelerated titration 
designs (26, 27).  This trial design minimizes the number of patients exposed to lower dose 
levels by using single-patient cohorts, reverting to a standard 3+3 design once a “stop decision” 
is taken.  Intra-patient dose escalation is permissible in the Simon design 3, and is separately 
described in Section 6.2. 
As of Amendment G (10/18/18), a “stop decision” was taken and the study reverted to a 
standard 3+3 design. 
Dose escalation proceeded initially with single patient cohorts per dose level, with 100% 
increments in dose level for the next single-patient cohort.  As of Amendment G (10/18/18), a 
“stop decision” was taken at Dose Level 6 to revert to the 3+3 dose-escalation cohorts.  The 
subsequent dose levels are 40% increments in the dose until a maximum dose is reached. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Levels  
Dose Level 
LMP744 mg/m2/day QD x 5 days every 28-days (IV) 
Level-1 
3 
Level 1 
6 
Level 2 
12 
Level 3 
24 
Level 4 
48 
Level 5 
96 
Level 6 
190 
Level 7 
260 
Level 8 
360 
Level 9 
500 
* 
Doses are stated as exact dose in units (mg/m2) 


24 
 
5.1.2 Dose Escalation Cohorts 
 
During the accelerated phase, there will be one patient per dose level.  The patient will be 
assessed for dose-limiting toxicity (DLT) and grade 2 toxicity (both parameters defined in 
Section 5.2) during cycle 1 of treatment. 
 
The accelerated phase of dose-escalation will end, and change to a standard 3+3 design, when: 
• one patient experiences DLT during cycle 1, OR 
• at the first instance of grade 2 drug-associated toxicity, when two additional patients will 
be enrolled.  If two different patients experience Grade 2 toxicity during cycle 1, the 
escalation plan will end.   
 
As of Amendment G (10/18/18), a patient on Dose Level 6 experienced DLT during cycle 1, and 
the study reverted to a standard 3+3 design. 
 
 
5.1.2.1 
Standard 3+3 Dose Escalation Phase 
 
In the standard phase of the dose escalation, 3 patients will be treated at the final accelerated 
dose level and initially at each new dose level.  Dose escalation will be based on DLTs observed 
during the first cycle of treatment.  If none of the 3 patients develop DLT at the dose 
administered, escalation will continue in cohorts of 3 patients each.  If a DLT during the first 
cycle is observed in any of the 3 patients, then the cohort will expand to 6 patients.  If a second 
DLT is observed during cycle 1, then up to a total of 6 patients will be enrolled to the next lower 
cohort.  If no more than 1 in 6 patients in a dose level have DLT during the first cycle, dose 
escalation is permitted.   
 
At the PI’s discretion, up to an additional 3 patients may be accrued at a dose level with 1 DLT 
observed among the 6 patients or no DLTs observed among the first 3 patients, to further assess 
safety.  Dose escalation will proceed if no additional DLTs are observed.  If 1 additional DLT is 
observed, the prior dose will be declared the MTD, once 6 patients have been treated with no 
more than 1 DLT observed.   
 
DLTs seen after the first cycle will not affect the dose escalation decisions. 
 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be declared the 
maximally administered dose (highest dose administered).  Three (3) 
additional patients will be entered at the next lowest dose level if only 3 
patients were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the next dose 
level. 
• If 1 or more of this group suffer DLT, then dose escalation is stopped, 


25 
 
and this dose is declared the maximally administered dose.  Three (3) 
additional patients will be entered at the next lowest dose level if only 
3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is generally the recommended phase 2 dose.  At least 6 patients 
must be entered at the recommended phase 2 dose. 
 
The MTD is the dose level at which no more than 1 in 6 patients experience DLT, and the dose 
below that at which ≥ 2 (of ≤ 6) patients have DLT as a result of the drug.  If ≥2 patients 
experience DLT on dose level -1 for LMP744, the study will be placed on hold and all data 
reviewed to make a decision about further evaluation of the study drug. 
 
 
5.1.2.2 
Expansion Cohort 
 
Once the MTD is identified, another 15 patients will be treated at the MTD on an expansion 
cohort.  With 15 patients and a biopsy QA failure rate of 50% with respect to paired biopsies, 
there is an 85% likelihood of having at least 6 usable samples and a 95% likelihood of having at 
least 5 usable samples. 
 
With Amendment L (date 6/7/2021), the MTD is identified as dose level 6 (190 mg/m2/day) and 
the expansion cohort will begin accrual. 
 
5.2 
Definition of Dose-Limiting Toxicity 
 
5.2.1 Grade ≥3 non-hematologic toxicity will be considered dose limiting, with the 
following exceptions: 
 
5.2.1.1 
Grade 3 fatigue lasting ≤ 7 days. 
 
5.2.1.2 
Grade 3 diarrhea will only be considered dose limiting if, after 48 hours, it 
is refractory to treatment as outlined in Section 5.3.2.  Grade 4 diarrhea will be dose 
limiting. 
 
5.2.1.3 
Grade 3 nausea and vomiting will be considered dose limiting after 48 
hours if it is refractory to maximal anti-emetic therapy and unable to be corrected to 
Grade 1 or baseline.  Grade 2 nausea or vomiting after 72 hours despite three anti-
emetogenic agents will also be considered dose limiting. 
 
5.2.1.4 
Grade 3 rise in creatinine, not corrected to Grade 1 or baseline after 
intravenous fluids within 24 hours, will be considered dose limiting.  All Grade 4 
rises in creatinine will be dose limiting. 
 
5.2.1.5 
Grade 3 electrolyte toxicities unable to be corrected to Grade 2 or baseline 
within 24 hours will be considered dose limiting.  
 
5.2.2 Grade 4 hematological toxicity will be considered dose limiting if it meets the criteria 
below.  Lymphopenia (any grade) will not be considered dose limiting for all 


26 
 
subjects. 
 
5.2.2.1 
Neutropenia: Grade 4 neutropenia for >5 days without fever or infection 
will be considered dose limiting.  Grade 4 neutropenia of any duration 
accompanied by fever or infection will be considered dose limiting.  
Twice weekly blood draws will be needed (after onset of grade 4 
neutropenia) to monitor duration of neutropenia for the first 2 cycles.  On 
subsequent cycles (cycle 3 and beyond), weekly blood draws will be 
monitored at the onset of grade 4 neutropenia. 
 
5.2.2.2 
Thrombocytopenia: Grade 4 thrombocytopenia will be considered dose 
limiting.  Grade 3 thrombocytopenia associated with bleeding will be 
considered dose limiting. 
 
5.2.2.3 
Anemia: Grade 4 anemia will be considered dose limiting. 
 
5.2.3 Any neurotoxicity Grade ≥2 that is not reversible to a Grade ≤1 within 2 weeks will 
be considered dose limiting.   
 
5.2.4 Any non-hematologic Grade 2 toxicity that does not resolve to Grade ≤1 or baseline 
within 14 days despite adequate treatment as described in Section 5.3 will be 
considered dose limiting, except for alopecia. 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
No other approved or investigational anticancer treatment will be permitted during the 
study period, including chemotherapy, biologic response modifiers, or immunotherapy.  
Palliative-intent single-fraction radiation therapy after cycle 1 is permissible at the PI’s 
discretion, but may not be administered concurrently with LMP744.  A delay of up to one 
week prior to starting a subsequent cycle of treatment will be permitted to enable marrow 
recovery.  No medications, including over-the-counter products, should be started 
without first consulting with the investigator. 
 
5.3.1 Vomiting 
Anti-emetics will not be administered prophylactically for the first dose, only for 
subsequent doses if nausea or emesis occurs.  However, if a patient develops 
nausea/vomiting, anti-emetics, such as Ondansetron will be instituted prior to treatment.  
If nausea or emesis persists, a second agent such as olanzapine or lorazepam should be 
added. 
 
 
5.3.2 Diarrhea 
Patients will not be given anti-diarrheal prophylactically.  If a patient develops diarrhea, 
if clinically indicated a test for C. difficile will be ordered.  If a patient is found to have 
C. difficile colitis, appropriate antibiotics will be instituted.  If noninfectious diarrhea 


27 
 
develops and does not have an identifiable cause other than study drug administration, 
anti-diarrheal (such as diphenoxylate HCl 2.5 mg + atropine sulfate 0.025 mg/tablet) 
dosed according to package insert or loperamide 4 mg PO after the first unformed stool 
with 2 mg PO every 2 hours as long as unformed stools continue (4 mg every 4 hours 
while asleep).  No more than 16 mg of loperamide should be taken in during a 24-hour 
period.  This regimen can be repeated for each diarrheal episode.  Diarrhea will be 
considered refractory if it does not resolve within 48 hours to Grade 2 with the above 
suggested regimens.   
 
5.3.3 Neutropenia 
Febrile neutropenia is a life-threatening complication and urgent broad-spectrum 
antibiotics, as well as an aggressive search for the source and microbial cause of the 
episode.  
 
Growth factors to prevent neutropenia will not be administered prophylactically.  If 
necessary, they may be administered according to accepted American Society of Clinical 
Oncology (ASCO) guidelines to allow re-treatment. 
 
5.3.4 Anemia 
Symptomatic anemia should be treated with red blood cell infusion, which is 
recommended if the hemoglobin falls below 8 g/dL.  The initiation of erythropoietic 
therapy for the management of chemotherapy-induced anemia follows the American 
Society of Hematology/ASCO clinical practice guidelines. 
 
5.3.5 Thrombocytopenia  
Thrombocytopenia will be treated conservatively.  In the absence of bleeding, fever, or a 
necessary invasive procedure, platelet transfusions should be given for a platelet count 
≤10,000/mm3.  If invasive procedure(s) is (28) planned, or the patient develops bleeding, 
platelet transfusions should be administered in accordance with the standard of practice, 
usually maintaining a platelet count above 50,000/mm3. 
 
5.3.6 Tumor lysis syndrome 
At the discretion of the PI, patients at risk of tumor lysis will receive allopurinol 24 hours 
prior to the initiation of therapy.  Additional measures such as hospitalization with 
aggressive iv hydration, use of rasburicase, and urinary alkalization will be used at the 
discretion of the investigator. 
 
5.3.7 Allergic Reaction  
If a patient develops hives or swelling, the LMP744 infusion will be held and at a 
minimum diphenhydramine administered at a dose of 50 mg IV.  Other medications (such 
as steroids or epinephrine) can be used at the discretion of the clinician.  Once the 
reaction has subsided, patients may be rechallenged with the original dose of LMP744.  
In case the reaction does not subside within 2 hours or the patient develops a subsequent 
reaction on rechallenge, the study drug will be discontinued and the patient taken off 
study.  A grade ≤ 2 allergic reaction will not be considered a DLT; pre-medication will be 
added to treatment on subsequent dosing if patients experience ≤ grade 2 infusion 


28 
 
reaction. 
 
5.3.8 Inhibitors and Inducers of ABCG2 and P-gp 
LMP744 is a substrate for ATP-binding cassette transporter protein ABCG2 and P-gp.  
Unless medically necessary, avoid the use of strong inhibitors and inducers of these 
transporters. 
 
5.3.9 Cytochromes P450 Inhibitors and Inducers, and Inhibitors of Drug Transporters 
The pathways by which LMP744 is eliminated are not known.  Unless medically 
necessary, avoid the use of strong inhibitors and inducers of all major drug metabolizing 
enzymes and drug transporters. 
 
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• DLT recurs after two dose reductions for DLT or no lower dose level exists (as described 
in Sections 5.1 and 6.2) 
• Patient decides to withdraw from the study 
• Noncompliance at the discretion of the PI 
 
5.5 
Duration of Follow Up 
 
Patients will be followed for 30 days after the last dose of study drug is administered or until one 
of the following occurs: patient enrolls on another protocol, patient receives standard of care, or 
death, whichever comes first.  The follow-up will consist of a phone call between Days 27-30 
after the last dose to evaluate adverse events that were ongoing and any new events that might be 
deemed related to the therapy.  Unacceptable toxicities (i.e., AEs related to the intervention) that 
have not resolved by Day 30 post-treatment will be followed via biweekly phone calls until 
stabilization or resolution. 
 
5.6 
Criteria for Removal from Study 
 
Patients will be removed from study for one of the following reasons: completed 30-day follow-
up period, toxicities are unresolved but stabilized, patient enrolls on another protocol, or patient 
receives other type of treatment-intent therapy.  The reason for study removal and the date the 
patient was removed must be documented in the medical record. 
 
 
6. DELAYS/DOSE MODIFICATIONS 
 
See below for dose delay and management guidance, indicating when the study agent should be 
held or discontinued due to specific adverse events.   


29 
 
 
6.1 
Drug-related toxicity 
 
6.1.1 If a patient has a DLT during cycle 1, no further treatment will be administered for 
that cycle and the dose will be reduced by one dose level for the next cycle. 
 
6.1.2 If the patient has a DLT during any subsequent cycle, no further treatment will be 
administered for that cycle and the dose will be reduced by one dose level for the next 
cycles and the patient will not be eligible for intra-patient dose escalation.   
 
6.1.3 If Grade 3 diarrhea occurs (increase of >6 stools/day over baseline) but resolved to  
≤ grade 2 with anti-diarrheal within 72 hours, the patient will receive the same dose 
on subsequent cycles with anti-diarrheal treatment as stated in Section 5.3.2.   If 
Grade ≥3 diarrhea continues > 72 hours despite treatment, this constitutes a DLT (see 
Section 5.2) and LMP744 will be dose reduced by one dose level for subsequent 
cycles. 
 
Diarrhea grade after 72 
hours of anti-diarrheal med 
Management/Next Dose for LMP744 
≤ Grade 1 
No change in dose 
Grade 2 
Resume at same dose level. 
Grade 3 
Hold* until ≤ Grade 2.  Resume at one dose level lower, if refractory.** 
Grade 4 
 
*Patients requiring a delay of >2 weeks will be taken off protocol therapy. 
**Patients requiring > two dose reductions will be taken off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose motion until diarrhea-free for 
12 hours (maximum dosage:  16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 
 
6.1.4 If Grade ≥2 nausea and vomiting require anti-emetics, the patient will receive anti-
emetics prior to the administration of subsequent doses of LMP744 as described in 
Section 5.3.1. 
 
Nausea grade after 72 
hours of antiemetic support 
Management/Next Dose for LMP744 
≤ Grade 1 
No change in dose 
Grade 2 
Resume at same dose level. 
Grade 3 
Hold* until ≤  Grade 2.  Resume at one dose level lower if refractory.** 
Grade 4 
Off protocol therapy 
* Patients requiring a delay of >2 weeks will be taken off protocol therapy. 
**Patients requiring > two dose reductions will be taken off protocol therapy. 
Recommended management: antiemetics. 
 
 
Vomiting grade after 72 
hours of antiemetic support 
Management/Next Dose for LMP744 
≤ Grade 1 
No change in dose 


30 
 
Vomiting grade after 72 
hours of antiemetic support 
Management/Next Dose for LMP744 
Grade 2 
Resume at same dose level. 
Grade 3 
Hold* until ≤   Grade 2.  Resume at one dose level lower, if refractory.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: antiemetics. 
 
6.1.5 Patients will be allowed to continue treatment for decreased leucocytes, ANC and 
hemoglobin that recover to a Grade ≤ 2 toxicity and platelets to Grade ≤ 1.  Dose 
reduction to one dose level lower may also be considered if ≥4 occurrences of 
symptomatic anemia requiring blood transfusion, at the discretion of the clinician. 
 
Neutropenia  
Management/Next Cycle 
≤ Grade 1 
No change in dose 
Grade 2 
 Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at same dose level. 
Grade 4 
Hold* until < Grade 2.  Resume at one dose level lower** 
*Patients requiring a delay of >2 weeks will be taken off protocol therapy. 
**Patients requiring > two dose reductions will be taken off protocol therapy. 
Use of growth factors per ASCO guidelines. 
 
Thrombocytopenia 
Management/Next Cycle 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 1.  Resume at one dose level lower, if indicated.** 
Grade 4 
Hold* until < Grade 1.  Resume at one dose level lower.** 
*Patients requiring a delay of >2 weeks will be taken off protocol therapy. 
**Patients requiring > two dose reductions will be taken off protocol therapy. 
 
Anemia 
Management/Next Cycle 
≤ Grade 1 
No change in dose 
Grade 2 
Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level lower, if indicated.  ** 
Grade 4 
Hold* until < Grade 2.  Resume at one dose level lower.** 
*Patients requiring a delay of >2 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
6.1.6 If a patient develops hives or swelling, the patient will receive at minimum 
diphenhydramine as described in Section 5.3.7.  Once the reaction has subsided, 
patients may be rechallenged with the original dose of LMP744.  In case the reaction 
does not subside within 2 hours or the patient develops a subsequent reaction on 
rechallenge, the study drug will be discontinued and the patient taken off study.  A 
grade ≤ 2 infusion reaction will not be considered a DLT; pre-medication will be 
added to treatment on subsequent dosing if patients experience ≤ grade 2 infusion 
reaction. 


31 
 
6.2 
Intra-patient Dose Escalation and De-escalation 
 
Intra-patient dose ESCALATION is permitted ONLY if:  
1. Patients did not experience toxicity >Grade 1 that is possibly, probably, or definitely 
related to the study drug after one cycle at the initial dose level (subsequent cycles may 
be delayed up to 14 days past the end of the previous cycle of 28 days to allow for 
toxicities to resolve). 
2. Higher doses have been evaluated and completed without a DLT. 
3. The patient’s disease has not progressed. 
4. There is no concern of cumulative toxicity. 
Doses may be escalated by one dose level for every subsequent cycle, provided conditions 1-4 
are met, up to the last evaluated dose level NOT associated with DLT. 
If a patient experiences DLT during a cycle, the dose will be REDUCED by one level (if there is 
a lower dose level, see Section 5.1.2) for the next cycle, provided toxicity has recovered to ≤ 
Grade 1 within 14 days after completing a 28-day cycle, and the patient’s disease is stable or 
responding.  If a patient is dose reduced twice and still experiences a DLT, then the patient 
would be removed from the study.  If no lower dose level exists, then the patient will be removed 
from the study.   
 
6.3 
Dose and Cycle delays 
 
Subsequent cycles may be delayed up to 14 days past the end of the previous cycle of 28 days for 
resolution of toxicity.  Patients will be allowed up to 2 dose reductions.  If more than 2 dose 
reductions are required, the patient will be removed from the study.  For patients on dose level 1, 
only 1 dose reduction will be allowed (see Section 5.1.2). 
 
6.4 
Reporting and Exclusions 
 
6.4.1 Evaluation of toxicity: A cycle is defined as being 28 days, with Day 1 starting the 
first day of the 5-day treatment.  .  All patients who receive a dose of LMP744 will be 
evaluable for toxicity regardless of whether they complete a cycle.  If therapy is 
delayed, the next cycle day 1 will be the day therapy is administered.  
 
Patients who do not complete a cycle of therapy for reasons other than toxicity will be 
replaced.   
 
6.4.2 Evaluation of response: All patients included in the study who receive any treatment 
at all will be assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible.  All patients who meet the eligibility 
criteria will be included in the main analysis of the response rate.  Secondary analyses 
may be restricted to patients without major protocol violations. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 


32 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
7.1.1 CAEPR for LMP744 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
LMP744 (NSC 706744) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
The CAEPR does not provide frequency data; refer to the Investigator's Brochure for this information. Below is the 
CAEPR for LMP744. 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 1.3, October 20, 20211 


33 
 
 
Adverse Events with Possible                                 
Relationship to LMP744                                     
(CTCAE 5.0 Term) 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
  
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
Nausea 
  
Vomiting 
  
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
Death NOS 
  
INVESTIGATIONS 
  
Alanine aminotransferase increased 
  
Aspartate aminotransferase increased 
  
GGT increased 
  
Lymphocyte count increased 
 Lymphocyte count increased (Gr 2) 
Neutrophil count decreased 
  
Platelet count decreased 
  
White blood cell decreased 
  
METABOLISM AND NUTRITION DISORDERS 
  
Hypokalemia 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
Hypoxia 
  
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. 
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
Animal Data: The following toxicities have been observed in animal studies with LMP744: 
 
Dogs 
 
Congenital, familial and genetic disorders - Increased levels of total bile acids; Inflammation of the portal tracts 
of the liver; Lethargy/fatigue; Low albumin; Microscopic biliary hyperplasia; Mononuclear cell inflammation 
suggestive of hemorrhagic cystitis 
General disorders and administration site conditions - Decreases in monocytes, basophils, RBCs, and/or large 
unstained cells; Fever; Gastrointestinal toxicities including vomiting and diarrhea; Hives in the inner ear; Increased 
levels of ALP 
Injury, poisoning and procedural complications - ALK increased; ALP increased; Anorexia; Arrhythmia; 
Aspiration/pulmonary infiltrates; Bile duct hyperplasia; Creatinine increased; Decreased bone marrow 
hematopoiesis; Decreased total eosinophils 
Investigations - Increased levels of fibrinogen; Nausea; Neutrophilia with left shift; Pain; Ptyalism; Skin toxicity; 
Supraventrical and nodal arrhythmia -- Sinus; Swollen leg; Tachycardia; Tarry feces; Weight loss 
 
Other 
General disorders and administration site conditions - Injection site toxicity including lesions, ulceration, 
necrosis, necrosis in the tail, inflammation; Liver toxicity; Lung toxicity; Decreased appetite; Hematological toxicity 
including lymphopenia and reticulocytopenia 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Allergic reactions/hypersensitivity 
including facial swelling and erythema of the eyes, face, legs; Bladder toxicity; Bone marrow toxicity; Decreased 
hematocrit counts 
 


34 
 
Rats 
General disorders and administration site conditions - Alopecia/scabbing; Decreased albumin; Decreased 
phosphorus; Decreased triglycerides; Elevated BUN; Emaciation; Increased globulin; Pulmonary thrombi; Red 
inguinal fur; Renal tubular degeneration; Rough coat 
Investigations - Thymic atrophy; Thymic toxicity; Tubular single cell necrosis 
 
 
Note: LMP744 in combination with other agents could cause an exacerbation of any adverse event currently known 
to be caused by the other agent, or the combination may result in events never previously associated with either 
agent. 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• ‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1) for expedited 
reporting purposes only.  ‘Expected’ AEs (the SPEER) are bold and italicized in the 
CAEPR (Section 7.1.1). 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm.  
These requirements are briefly outlined in the tables below. 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 


35 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” in 
the system organ class (SOC) “General disorders and administration site conditions.”  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (24) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
electronic submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 


36 
 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
Lymphopenia (any grade), alopecia (any grade), anemia (grade 2), electrolytes (grade 2: 
sodium, potassium, phosphorous, and magnesium), albumin (grade 2), hyperuricemia 
(grade 3), INR (grade 2), and PTT (grade 2) will not be reported via CTEP-AERS but 
will be included in the routine data submissions.   
 
 
7.3.5 NIH Reporting Requirements/ Data and Safety Monitoring Plan  
 
7.3.5.1 
Definitions 
 
Please refer to definitions provided in Policy 801: Reporting Research Events 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs).   
 
7.4 
OHSRP Office of Compliance and Training / IRB Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events, and Policy 
802: Non-Compliance in Human Subjects Research (found in 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs). Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies. 
1.1.1 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here: 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs  


37 
 
7.5 
NCI Clinical Director Reporting 
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director.  
 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
 
To report these deaths, please send an email describing the circumstances of the death to the 
Clinical Director/designee at NCICCRQA@mail.nih.gov within one business day of learning of 
the death. 
 
7.5.1 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  CTEP requires all 
secondary malignancies that occur following treatment with an agent under an NCI IND be 
reported via CTEP-AERS.  Three options are available to describe the event:  
 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS)  
• 
Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.5.2 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified.  
 
 
8. PHARMACEUTICAL INFORMATION  
 
LMP744 (NSC 706744) 
 
Chemical Name:  6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-
8,9-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline hydrochloride 
 
Classification:  Indenoisoquinoline 
 
Molecular Formula:  C24H25ClN2O7 
M.W.:  488.92 (HCl salt) 
 


38 
 
Mode of Action:  Inhibition of topoisomerase 1 
 
How Supplied:  LMP744 is supplied by the DCTD, NCI and distributed by the Pharmaceutical 
Management Branch, NCI as sterile, non-preserved, single-use glass vials sealed 
with rubber stoppers and aluminum crimp seals and flip-top caps. Each vial 
contains 15 mg/15 mL or 50 mg/50 mL of LMP744 (1 mg/mL) in Water for 
Injection as a clear, dark red solution, pH~2.8. pH is adjusted with hydrochloric 
acid. 
 
Preparation:   LMP744 solution for infusion may be diluted with 5% Dextrose Injection, USP 
(D5W) to concentrations ≥ 0.3 mg/mL or may be transferred to an empty infusion 
container and administered undiluted.  Discard unused vial portion after use. 
  
LMP744 solution for infusion is compatible with non-PVC and non-DEHP 
containing infusion containers and non-DEHP infusion sets. 
 
Storage:   
Store intact vials refrigerated (2oC – 8oC). 
 
If a storage temperature excursion is identified, promptly return LMP744 to between 
2-8°C and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) 
to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:   
Shelf life testing of the intact vials is on-going.  Prepared solutions for infusion 
should be administered within 4 hours of preparation if stored at room temperature 
or within 24 hours if stored refrigerated. 
 
Route of Administration:  Intravenous 
 
Method of Administration: Intravenous as a 1-hour infusion.  A central line is required for 
administration. 
 
Potential Drug Interactions:  LMP744 is a substrate for ATP-binding cassette transporter protein 
ABCG2 and P-gp and potentially subject to drug interactions. 
 
 
8.1 
Agent Ordering and Agent Accountability 
 


39 
 
8.1.1 NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application.  Access to OAOP requires the establishment of a CTEP 
Identity and Access Management (IAM) account and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time.  Refer to the PMB’s website for 
specific policies and guidelines related to agent management.   
 
8.1.1.1 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing, and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation, and ordering investigator on this 
protocol. 
 
8.2 
Investigator Brochure for LMP744 
 
The current version of the IB will be accessible to site investigators and research staff through 
the PMB Online Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the maintenance 
of an “active” account status and a “current” password.  Questions about IB access may be 
directed to the PMB IB coordinator via email. 
 
8.3 
Useful Links and Contacts 
 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  


40 
 
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
• CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between  
8:30 am and 4:30 pm (ET) 
 
9. CORRELATIVE STUDIES 
 
9.1 
Pharmacokinetics 
 
Blood Samples 
Blood samples for PK analyses will be collected at the following timepoints in cycle 1 only:  
• Day 1, prior to drug administration, 2 minutes (+/- 2 minutes) before end of infusion, and 
at appropriate time points post infusion (15 minutes, 30 minutes, and 1, 2, 4, and 6 hours 
post infusion) 
• Day 2, 24 hr post day 1 start of infusion (immediately prior to day 2 infusion), and 
2 minutes (+/- 2 minutes) before end of infusion 
• Day 3, 24 hr post day 2 start of infusion (immediately prior to day 3 infusion), and 
2 minutes (+/- 2 minutes) before end of infusion 
• Day 4, 24 hr post day 3 start of infusion (immediately prior to day 4 infusion), and 2 
minutes (+/- 2 minutes) before end of infusion 
• Day 5, 24 hr post day 4 start of infusion (immediately prior to day 5 infusion), and 2 
minutes (+/- 2 minutes) before end of infusion 
• Day 8, 72 hr post day 5 start of infusion  
 
The total volume of blood collected for PK studies during the initial treatment cycle is 
expected to be < 50 mL per patient.  Based on results from initial measurements, sampling 
times may be adjusted, but neither the total number of samples nor the total amount of blood 
drawn per patient will be increased.    
 
Samples will be collected in K2-EDTA tubes with 3 mL of blood per sample.  Samples 
should be kept on ice until centrifugation.  All samples will be centrifuged at 2000×g at 4°C 
for 10 minutes and plasma will be stored at -70℃ for analysis.  Samples will be analyzed 
using a validated LC-MS or LC-MS/MS method for LMP744 in human plasma.  The plasma 
concentration-time data will be analyzed using the WinNonlin (Pharsight, Mountain View, 
CA) or other appropriate PK software.  The maximum plasma concentration, time to 
maximum concentration, AUC extrapolated to infinity, and apparent terminal half-life will be 
calculated by non-compartmental analysis.   
 
The parent drug molecule and possibly metabolites in plasma will be analyzed by the 
Molecular Therapeutics/Drug Discovery Program at the University of Pittsburgh Cancer 
Institute.  This facility has extensive experience in the measurement of drugs and metabolites 


41 
 
in body fluids.  The laboratory has multiple HPLC instruments, including ultraviolet 
absorption detectors and several single- and triple-quadrupole mass spectrometers.   
 
Plasma samples for PK analysis will be sent to: 
 
Jan H. Beumer, PharmD, PhD 
University of Pittsburgh Cancer Institute 
Room G27E, Hillman Research Pavilion 
5117 Centre Avenue 
Pittsburgh, PA 15213-1863 
 
Please notify Robert Parise (parisera@upmc.edu) and Susan Christner (christners@upmc.edu) 
(phone: 412-623-3248) at least 24 hours prior to shipment.  An alternate qualified analytical site 
(DTP or DTP contractor’s site) may be used, if necessary, for timely analysis of all samples. 
 
9.2 
Pharmacodynamics 
 
We plan to evaluate the in vivo molecular effects of LMP744 in CTCs and tumor biopsy 
specimens.  
 
9.2.1 Biopsy procedure and processing 
 
The timing of tumor biopsy samples will be at baseline (pre-treatment) and on day 2 (1-4 
hours after the LMP744 infusion).  Based on initial results from the trial, tumor biopsy 
timing may be adjusted, but the number of biopsies will not be increased without an 
amendment.  Tumor biopsies will be mandatory during the expansion phase. 
 
Biopsies will be obtained on selected patients when lesions are safely accessible 
(including cutaneous, subcutaneous, and easily accessed parenchyma lesions). 
 
Serial tumor biopsies will be obtained by the Interventional Radiology team by a 
percutaneous approach (if a SQ lesion is identified, biopsies may be obtained by a 
surgeon or dermatologist).  It is preferred that up to 5 core biopsies ≥18 gauge in diameter 
and ≥1 cm in length will be obtained during each procedure if considered safe and 
feasible.  If a site is deemed appropriate for biopsy with minimal risk to the participant by 
agreement between the investigators and Interventional Radiology team, an attempt for 
biopsy will be made.  The use of imaging to facilitate biopsies will be decided by 
members of the Interventional Radiology team and may include ultrasound, CT scan, or 
MRI.  Should a CT scan be needed for biopsy, the number of scans for each procedure 
will be limited to the minimum number needed to safely obtain a biopsy.  Tumor biopsies 
and local anesthesia will be administered only if they are considered to be of low risk to 
the participant, as determined by the investigators and Interventional Radiology.   
 
 
If the participant chooses not to undergo the day 2 tumor biopsy, he/she will still remain 
in the study and receive study medication, and all the other correlative studies will be 
performed.   


42 
 
 
If an initial attempt at percutaneous biopsy is unsuccessful, the participant will be given 
an option to proceed with a repeated attempt at percutaneous biopsy.  In case biopsy 
samples cannot be obtained for a given participant, the participant will still remain in the 
study and receive study medication, and all the other correlative studies will be 
performed. 
 
Up to 5 core biopsies will be obtained at each time point and processed according to the 
National Clinical Target Validation Laboratory (NCTVL) SOP 340507 
(https://dctd.cancer.gov/ResearchResources/biomarkers/docs/par/ 
SOP340507_Biopsy_Frozen.pdf).  Briefly, cores will be transferred into a 1.5-mL pre-
chilled cryovial and then flash frozen in liquid nitrogen.  Biopsies should be collected, 
placed in prechilled cryogenic vials, and frozen within 2 minutes of collection.  
 
The frozen biopsy specimens should be transferred to PADIS on dry ice, where the core 
biopsy samples are stored at -80°C until processing.  Biopsies for PD analysis will be 
shipped via FedEx to: 
 
Attention: Leroy Smith 
NCI-F/FNLCR 
Natural Products and Tumor Repositories | Charles River 
1073 Beasley Street, Building 1073 
Fort Detrick 
Frederick, MD 21702 
Phone: 301-846-5748 
NCI_PD_Support@mail.nih.gov 
 
For NCI Clinical Center specimens only: Shipment should be by CSP Courier and may 
be arranged by contacting Jenn Bangh, FNLCR, Tel.: 301-846-5893 
 
Frozen biopsy samples will be used for molecular analysis, including γH2AX and cleaved 
caspase-3 measurement (apoptosis; as described in Section 2.4.1), LC-3 (autophagy), 
epithelial-mesenchymal transition (EMT) analysis, and DNA damage response (DDR) 
analysis.  The EMT panel will analyze the fraction of CTCs that are positive for vimentin 
and/or cytokeratin in conjunction with a tumor marker (UC1, CEA, or TFE1, depending 
on tumor histology).  The DNA damage response (DDR) panel will analyze levels of 
ERCC1, RAD51, pATR, pNbs1, Topo1cc, Top1, and SFLN11 proteins involved in the 
repair of DNA breaks.      
 
If for some reason only one core is able to be obtained, the core will be divided, with half 
submitted to Surgical Pathology and half used for PD studies.  Priority will be given to 
performing γH2AX and cleaved caspase-3 analysis on paired biopsy samples. 


43 
 
 
9.2.2 Circulating tumor cells (optional) 
 
For the current protocol, optional blood for CTCs will be collected from patients at the 
following timepoints: 
• baseline (prior to drug infusion) 
• on day 3 of cycle 1 (within 2 to 4 hours after the start of LMP744 infusion) 
• on day 1 of every subsequent cycle (prior to drug infusion) 
• at time of disease progression  
 
These samples will be used to determine:    
 
1)  The number of CTCs in the blood sample 
2)  Whether the level of γH2AX expression has increased (assessing the fraction of 
γH2AX expression in CTCs via immunofluorescence)   
3)  The dose response in the fraction of CTCs that is γH2AX positive 
4)  EMT panel (as described above)  
 
These values will be compared to baseline values collected from samples from the same 
patient.  At the NCI clinical center, each blood specimen (7.5 mL) will be collected into 
one 10 mL Streck tube (catalog number 218962).  One 10 mL RareCyte tube (catalog 
number 24-1070-005) is also acceptable.  Tubes must be inverted 8 times to ensure 
adequate mixing of the additive.  At other participating sites, each blood specimen will be 
collected into one 7.5-mL CellSave tube or one 10 mL Streck tube as described in 
Appendix D (kits will be provided).  Refer to NCI DCTD SOP LHTP003.08.19 for 
additional guidance regarding blood collection in a Streck tube: 
https://dctd.cancer.gov/ResearchResources/biomarkers/emt/LHTP003.08.19_Streck.pdf 
 
Blood for CTC analysis will be shipped at room temperature to the PADIS laboratory on 
the day it is collected as described in Appendix D.  Samples may not be held at the 
external site or shipped with frozen biopsy samples.  Prior to CTC collection, each 
outside participating site should e-mail a request for specimen collection and 
shipping materials from NCI_PD_Support@mail.nih.gov.   
 
At NCI only: arrangements will be made for pickup with the CSP courier service.  At 
least 24 hours prior to blood sample collection, the research nurse will contact the NCI 
Phase I/II PK/PD Support Group in NIH Building 10: E-mail (preferred): NCIPK-
PDsupportgroup@mail.nih.gov; Pager (preferred): 102-12798; Phone: 240-858-3963; 
Fax: 301-480-5871.  The NCI Phase I/II PK/PD Support Group will arrange for same day 
processing or immediate shipment to FNLCR; specimens should be held at controlled 
room temperature (15˚C to 30˚C) prior to processing. 
 
 
 


44 
 
9.2.3 At NCI only: Blood collection for ctDNA analysis in expansion phase patients 
 
9.2.3.1 
Timing of ctDNA blood collection 
 
Plasma, derived from whole blood collected from expansion cohort patients (as of 
Amendment Q, 6/14/22), will undergo ctDNA assessment by the TSO500 panel to 
quantitatively assess longitudinal changes in ctDNA levels (as a percentage of total 
circulating, cell-free DNA) and to identify any tumor genomic alterations that may be 
associated with response or resistance to the LMP744 treatment; the results of these 
studies will not be returned to patients.  Once a patient has come off study, ctDNA 
from blood samples correlating to clinically informative time points (minimally, 
before treatment and at restaging scans suggesting tumor growth) will be analyzed. 
 
Three whole blood samples of at least 7.5 mL each will be collected into three 
respective 10-mL Streck tubes at each of the following time points and shipped to 
MoCha within 3 days for ctDNA analysis: 
• baseline (pre-treatment; up to 8 days prior to the start of treatment and within ± 8 
hours of the biopsy at this time point) 
• day 1 of every subsequent cycle (at any time) 
• at time of disease progression 
 
9.2.3.2 
Blood specimen shipping for ctDNA analysis 
 
Labeling: 
Blood specimens should be labeled with: 
• Sample type (e.g., whole blood) 
• Time point (e.g., C1D1 pre-dose) 
• Collection date and time 
• Sample ID, containing: 
o CTEP protocol number 
o Site LAO code 
o Unique patient ID (Do NOT include patient name, medical record number, 
or initials) 
o Consecutive 800-series sample collection number (i.e., 800, 801, 802) 
 The 2 tubes for each time point should be designated using “A” and “B” (e.g., the 
two pretreatment specimens should be labeled 800A and 800B). 
For example, the sample ID for the C1D1 pre-dose ctDNA blood sample collected on 
Study 10002 for NCI DTC patient #004 should be: 100002_NCIDTC_004_800. 
 
Ship blood specimens at ambient temperature to:  
Attn: Gloryvee Rivera 
MoCha Histology Lab 
Frederick National Laboratory for Cancer Research 
Leidos Biomedical Research, Inc. 


45 
 
1050 Boyles Street 
Building 321 Room 107 
Frederick, MD 21702 
MoChaSampleReceiving@nih.gov 
 
Shipment should be by CSP Courier and may be arranged by contacting Mike 
Johnston, FNLCR, Tel.: 301-846-5893. 
 
Please contact Alyssa Chapman at 301.846.1718 (MoChaSampleReceiving@nih.gov) 
to ask any questions regarding storage or shipment of these specimens.  MoCha 
should be notified as soon as possible of all protocol deviations or issues, prior to 
shipment of specimens(s). 
 
Samples should arrive at MoCha within 2 days of collection when possible; 
arrival within 3 days of collection is permissible when necessary.  Note that 
FNLCR receiving is closed and unable to receive samples on weekends and on all 
Federal holidays. 
 
 
10. STUDY CALENDAR 
 
Eligibility screening evaluations (see Section 3.4) are to be performed within 8 days prior to 
patient enrollment, with the exception of informed consent, ECHO, and tumor imaging scans, 
which must be performed within 28 days prior to patient enrollment.  Baseline history, physical 
examination, laboratory evaluations, urinalysis, and EKG are to be conducted within 8 days prior 
to start of protocol therapy.  If protocol therapy is started within 8 days of the screening 
evaluations, values from the screening evaluations may be used as baseline measurements.  If >8 
days have passed since the screening evaluations, the medical history, physical examination, 
laboratory evaluations, urinalysis, and EKG must be repeated prior to starting protocol therapy.  
Baseline imaging scans and ECHO must be done within 28 days prior to the start of protocol 
therapy.   
 
After cycle 2, the start of a new cycle may begin up to 3 days earlier than it would otherwise be 
scheduled or be delayed up to 1 week to accommodate scheduling conflicts and other unexpected 
events.  History and physical examination and laboratory evaluations can be performed up to 3 
days before the start of the next cycle.  In the event that the patient’s condition is deteriorating, 
laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of 
therapy. 
 
 


46 
 
 
Pre-Study 
Screening 
C1
D1 
C1 
D2 
C1 
D3 
C1
D8 
C1
D15 
C2 
D1 
C2 
D15 
C3 
D1 
C3 
D15 
Time of 
progression 
LMP744* 
 
X 
 
 
 
 
X 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X----------------------------------------------------X 
 
Physical examc 
X 
 Xi 
 
 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
 Xi 
 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 Xi 
 
 
X 
 
X 
 
X 
 
X 
Performance status 
X 
 Xi 
 
 
 
 
X 
 
X 
 
X 
CBC w/diff, pltsa 
X 
 Xi 
 
 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
 Xi 
 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysisa 
X 
 Xi 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse event evaluation 
 
X----------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated per Section 
11.1.  Documentation (radiologic) must be 
provided for patients removed from study for 
progressive disease. 
X 
B-HCGb 
X 
 
 
 
 
 
X 
 
X 
 
 
PK sampling-bloodd 
 
X 
 
 
X 
 
 
 
 
 
 
Blood for CTCse 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Blood for ctDNAf 
 
X 
 
 
 
 
X 
 
X 
 
X 
Tumor biopsiesg 
 
X 
X 
 
 
 
 
 
 
 
 
ECHO/EKGh 
X 
Xi 
 
 
 
 
 
 
X 
 
 
*: LMP744 will be administered via central line. Doses as assigned; days 1-5 intravenously over 1 hour; dose 
escalation as defined in Section 5. After cycle 1, the infusion may be administered over 1 hour +/- 10 minutes. 
After cycle 2, a new cycle may begin up to 3 days earlier than it would otherwise be scheduled or be delayed up to 
1 week.  Monitor patients in clinic for allergic/hypersensitivity reactions for a minimum of 1 hour after receiving 
drug during cycle 1 and as clinically indicated thereafter.   
a: 
Labs (albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
phosphorus, potassium, total protein, SGOT (23), SGPT (10), TSH, sodium, GGT) and urinalysis will be performed 
at baseline/D1 of cycle 1, D8 and D15 of cycle 1, D1 and D15 of cycles 2 and 3, and then only at the start of each 
cycle (up to 3 days before start of a new cycle). For patients with lymphoma only, uric acid and LDH will be 
performed on a similar schedule.  Patients on the expansion cohort will also have coagulation profile performed per 
Section 3.4. 
b: Urine or serum pregnancy test (women of childbearing potential) prior to every cycle. 
c: 
History and physical, including vital signs and weight, during weeks 1 and 2 of cycle 1, and at the start of each 
cycle thereafter (within 3 days prior to treatment).   
d:    Blood samples for PK analyses will be collected per Section 9.1.  
e: 
Blood for circulating tumor cells (optional) will be collected at baseline, on cycle 1 day 3, at the start of every 
subsequent cycle, and at disease progression per Section 9.2.2.  


47 
 
f:     Blood samples for analysis of circulating tumor DNA (ctDNA) will be collected at baseline (pre-treatment, up to 8 
days prior to the start of treatment and within ±8 hours of the biopsy at this time point), on cycle 1 day 2, on day 1 
of every subsequent cycle (at any time), and at time of disease progression. 
g: Tumor biopsies will be collected at baseline (pre-treatment) and on cycle 1 day 2 post therapy per Section 9.2 
(mandatory during the expansion phase).  
h:    EKG and ECHO at baseline, up to 1 week prior to cycles 3 and 5, and as clinically indicated thereafter. 
i:    Values from eligibility screening evaluations may be used as baseline (C1D1) values if test was performed within 8 
days of start of protocol therapy (within 28 days of start of protocol therapy for ECHO).  See Sections 3.4 and 5. 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect 
 
11.2 
Solid Tumors 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  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. 
 
Patients should be re-evaluated for response every 2 cycles (every 3 cycles for patients on study 
for more than 1 year; every 4 cycles for patients on study more than 3 years).  In addition to a 
baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. 
 
11.2.1 Definitions 
 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their 
first treatment with LMP744. 
 
Evaluable for objective response:  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.2.2 Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 


48 
 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.   
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  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 [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, 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 
patient, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for 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.  


49 
 
 
11.2.3 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 (≥1 cm) 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 (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g., for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 


50 
 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 


51 
 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.2.4 Response Criteria 
 
11.2.4.1 
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 (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum 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 (0.5 cm).  
(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 diameters while on 
study. 
 
11.2.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 


52 
 
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). 
 
11.2.4.3 
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 patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients 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 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not evaluated 
No 
SD 
Documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after discontinuation of treatment. 
 
For Patients 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 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 


53 
 
∗ 
‘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 
 
11.2.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.3 
Lymphomas 
 
11.3.1 Complete response (CR): Disappearance of all signs and symptoms of lymphoma for 
a period of at least one month.  All lymph nodes and nodal masses must have 
regressed to normal size (≤1.5 cm in their greatest transverse diameter for nodes > 1.5 
cm before therapy).  Previously involved nodes that were 1.1 to 1.5 cm in their 
greatest transverse diameter before treatment must have decreased to ≤1 cm in their 
greatest transverse after treatment or by more than 75% in the sum of the products of 
the greatest diameters.  The spleen, if consider to be enlarged before therapy on the 
basis of a CT scan must have regressed in size and must not be palpable on physical 
examination.  Any macroscopic nodules in any organs detectable on imaging 
techniques should no longer be present.  
 
11.3.2 Complete response unconfirmed (CRu): A residual lymph node mass > 1.5 cm in 
greatest transverse diameter that has regressed by > 75% in sum of the products of the 
greatest diameters, does not change over the last two treatments, has a negative PET 
scan, and any biopsies obtained are negative will be considered to be in CR.  In 
organs involved by disease, any residual lesions that have decreased by > 75% in sum 
of the products of the greatest diameters or are < 1 cm, are consistent with scar, and 
stable over the last two treatments will be considered to fulfill criteria for CR. 
 
11.3.3 Partial response (PR): 50% or greater decrease in the sum of the products of the 
longest perpendicular diameters of all measured lesions lasting for a period of at least 
one month.  No individual lesions may increase in size and no new lesions may 
appear. 
•Patients in PR with an estimated >80% reduction in initial tumor bulk whose measurable 
disease does not change between cycles 4 and 6, and have a negative PET scan after 
cycles 4 or 6 will be considered to be in clinical CR. 
 


54 
 
11.3.4 Stable disease (SD): Tumor measurements not meeting the criteria of CR, PR, or PD. 
 
11.3.5 Progression (PD): Increase of 25% or more in the sum of the products of the longest 
perpendicular diameters of all measured lesions compared to the smallest previous 
measurements, or the appearance of any new lesion(s). 
 


55 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.  
 
12.1 
Data Reporting 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding 
Organization or Participating Organization roster at the enrolling site. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Training will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.1.1 Method 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/CTMS.  On-site audits will be conducted three times annually 
(one annual site visit and two data audits).  For CTMS monitored studies, after users have 
activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by 
email at ctms@theradex.com for additional support with Rave and completion of CRFs. 
 
12.2 
NIH Required Data Safety and Monitoring Plan 
The investigators at each participating center will be responsible for the collection, maintenance, 
and quality control of the study data.  Adverse events observed in patients enrolled on the trial 
will be monitored in real time by the Principal and Associate Investigators, and attribution of 
these events to the research will be determined at the end of each treatment cycle in each subject.  
The clinical research team (PI, associate investigators, research nurses, data managers) will meet 
weekly when patients are being actively treated on the trial to discuss each patient in detail and 
ensure that all events are graded appropriately, and that the attribution to study drug is correct.  


56 
 
The Coordinating Center is responsible for establishing conference calls between participating 
sites at least on a monthly basis to discuss the observed toxicities and protocol issues.  
 
All SAEs will be reported through CTEP-AERS to CTEP, to the Coordinating Center PI at NCI, 
and forwarded to the IRB per Section 7.  In all cases where the dose of the study treatment has 
been reduced/modified or the patient withdrawn due to unusual or unusually severe toxicity 
considered related to the study treatment, the investigator must contact and inform the 
Coordinating Center PI.  All sites will be monitored by the CTEP drug monitor, who will receive 
data from all participating sites. 
 
Data will be monitored regularly by the PI in order to identify significant toxicity trends.  Any 
new significant finding that may affect the patient’s willingness to continue in the study will be 
shared with patients.   
 
Confidentiality will be maintained as much as possible, consistent with applicable regulations.  
Names of participants or identifying material will not be released without patient permission, 
except when such release is required by law.  No patient’s name or identifying information will 
be released in any publication or presentation.  Records are maintained according to current legal 
requirements, and are made available for review according to the requirements of the FDA or 
other authorized user, only under guidelines established by the Federal Privacy Act.  
 
Safety Monitoring Committee: 
Because this is a multi-institutional protocol for which the NCI CCR is the Coordinating Center, 
it will be monitored by the DTC Safety Monitoring Committee, NCI.  
 
12.3 
Multicenter Guidelines 
 
This protocol will open initially at the NCI.  The NIH IRB will be notified once the participating 
centers’ IRBs have approved the studies to open.  This protocol will follow the CCR’s Clinical 
Research Operations’ SOPs for multicenter trials.  
 
12.3.1 IRB Approvals  
As the Coordinating Center for a trial, it is the PI’s responsibility to ascertain that no patients are 
entered on the trial at a participating institution without full IRB approval.  Thus, the NIH IRB 
must approve the addition of each participating institution to the protocol and will require a copy 
of the local IRB approval from each participating institution before NIH IRB approval will be 
granted. 
  
The PI will provide the NIH IRB with a copy of the participating institution’s approved yearly 
continuing review.  Registration will be halted at any participating institution in which a current 
continuing approval is not on file at the NIH IRB.  
 
12.3.2 Amendments and Consents  
The NCI PI will provide the NIH IRB with copies of all amendments, consents, and approvals 
from each participating institution. 
 


57 
 
12.3.3 Data Collection 
The investigators will be responsible for the collection, maintenance, and quality control of the 
study data.  Each site investigator is also responsible for maintaining all source documentation 
related to the study, including any films, tracings, computer discs or tapes.  NCI will be 
responsible for data management, data analysis, and reporting.  Data collection forms will be 
provided to the participating institutions.  Required data include, not exclusively: prior disease-
related therapies with dates, disease type, stage, disease sites, with measurements, and concurrent 
medications.  
 
12.3.4 Human Data Sharing Plan 
What data will be shared?  
We will share human data generated in this research for future research as follows: 
x De-identified data in an NIH-funded or approved public repository  
x Identified data in BTRIS (automatic for activities in the NIH Clinical Center)  
x De-identified or identified data with approved outside collaborators under appropriate 
agreements  
 
How and where will the data be shared?  
Data will be shared through:  
x An NIH-funded or approved public repository: clinicaltrials.gov 
x BTRIS (automatic for activities in the NIH Clinical Center)  
x Approved outside collaborators under appropriate individual agreements  
x Publication and/or public presentations  
 
When will the data be shared?  
x At the time of publication or shortly thereafter 
 
12.3.5 Data and Center Audits 
Audits will be conducted yearly to ensure data integrity and provide quality control.  These 
audits will be conducted by the NCI research team.  Selected patient charts should be audited as 
well as the participating institution’s Standard Operating Procedures (SOP) at the time of the 
visit.  Data from participating institutions should be available when the protocol is audited at the 
NCI.  
 
12.4 
CTEP Multicenter Guidelines  
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 


58 
 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) (except for Group studies). 
12.5 
Collaborative Agreements Language 
 
N/A 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
The primary objective of this trial is to establish the safety, tolerability, and MTD of LMP744 
administered intravenously daily for 5 days in 28-day cycles, to patients with refractory solid 
tumors.  This study will follow design 3 of the Simon accelerated titration designs (26), with 
dose escalation proceeding in 1-patient cohorts and switching to standard 3+3 dose escalation of 
dose levels when specific criteria are met (Section 5.1.1).  (Note: As of Amendment G 
[10/18/18], the study switched to standard 3+3 dose escalation.  As of Amendment I [9/25/19], 
there is flexibility to accrue up to an additional 3 patients on any dose level that has 1 DLT 
observed among 6 patients [see Section 5.1.2.1].  As of Amendment L [date 6/7/2021], the MTD 
has been identified and the expansion cohort will begin accrual [see Section 5.1.2.2].) 
 
Following this, another 15 patients will be treated at the MTD on an expansion cohort, which 
will include mandatory biopsies.  With 15 patients and a tumor biopsy QA criteria failure rate of 
50% with respect to paired (pre- and post-dose) biopsies, we have an 85% likelihood of having at 
least 6 usable PD samples, and 95% likelihood of having at least 5 usable samples from the 
expansion cohort.  Biopsy tissue quality will be monitored and accrual to the expansion phase 
will stop once we have obtained 6 usable paired samples.  With 6 PD sample pairs, there is 90% 
power to detect a treatment effect equivalent to 1.85 SD’s (associated with the intra-patient 
baseline variability of the PD marker) with the paired 2-sample T-test, at the 1-sided .05 
significance level, for a given PD variable of interest.  PD variables may be log-transformed to 
achieve more nearly normal distributions. 
 
DLTs will be summarized descriptively according to dose level.  In addition, the relation of dose 
level with presence or absence of DLT will be analyzed using logistic regression, as described by 
Simon (20).  
 
All AEs will be tabulated by type and grade according to dose level.  In addition, the presence or 
absence of grade 2 or higher toxicity for each patient in each treatment cycle will be modeled 
using random effects logistic regression as described by Simon (20), incorporating dose during 
the cycle and total dose for previous cycles, with intra-patient random effects.   
 
 
13.2 
Sample Size/Accrual Rate 
 
As of Amendment G (10/18/18), if all dose levels are evaluated, we anticipate enrolling a 
minimum of 35 patients and a maximum of 47 patients.  In order to allow for a small number of 
patients who may not be evaluable, the accrual ceiling for this trial is set at 53 patients.  


59 
 
 
It is anticipated that 1 patient may be enrolled per month onto this study during the accelerated 
titration stage (already completed) and 1-2 patients/month thereafter.  It is expected that 25-35 
months will be required to accrue the number of patients necessary to complete the trial. 
 
13.3 
Analysis of Secondary and Exploratory Endpoints 
 
Exploratory evaluations will be performed, with results reported with appropriate caveats about 
the exploratory nature of the analysis, and without formal adjustment for multiple comparisons. 
 
14. HUMAN SUBJECTS PROTECTION 
 
14.1 
Rationale for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met.  For safety reasons, pregnant women 
and children are excluded from this study.  The NCI is the coordinating center for this multi-
institutional study.  This study will be recruited through internal referral, our physician referral 
base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-
800-4Cancer.)  Participants should realize that there is no guarantee of benefit to them from 
participation in this trial.  The results of this trial may benefit future cancer patients.  To date, 
there is no information that suggests that differences in drug metabolism or effect on tumor 
would be expected in one ethnic group compared to another.  Efforts will be made to extend 
accrual to each representative population, but a balance must be struck between participant safety 
considerations and limitations on the number of individuals exposed to potentially ineffective 
treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on 
the other hand.  If differences in outcome that correlate to ethnic identity are noted, a follow-up 
study may be written to investigate those differences more fully. 
 
Inclusion of Women and Minorities:  
This study will be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met. 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
1 
0 
0 
0 
1 
Asian 
2 
3 
0 
0 
5 
Native Hawaiian or 
Other Pacific Islander 
1 
1 
0 
0 
2 
Black or African 
American 
7 
7 
1 
0 
15 
White 
12 
13 
2 
2 
29 
More Than One Race 
0 
1 
0 
0 
1 
Total 
23 
25 
3 
2  
53 


60 
 
 
14.2 
Justification for Exclusions 
Due to lack of knowledge on the effects of LMP744 on the fetus or infants, as well as the 
possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial.  
Participants with unstable or serious medical conditions are due to the possibility that the 
underlying condition may obscure the attribution of adverse events to study drug.   
 
14.3 
Participation of Children   
Participants under the age of 18 will be excluded from study because no dosing or adverse event 
data are currently available for the use of LMP744 in participants <18 years of age.  
 
14.4 
Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence 
of any of a range of side effects that are listed in the consent document.  The procedure for 
protecting against or minimizing risks will be to medically evaluate patients as described in 
Section 10.  Although no compensation is available, any injury will be fully evaluated and 
treated in keeping with the benefits or care to which participants are entitled under applicable 
regulations.  
 
14.4.1 Procedure for Protecting Against or Minimizing Any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature 
and severity.  This study may involve risks to patients, which are currently unforeseeable.  
All patients will be monitored for side effects from taking study medication and from 
undergoing biopsy and blood sampling procedures.  
 
14.4.2  Radiation Risks 
As biopsies will be performed with CT guidance, this research study involves exposure to 
radiation from up to 2 CT scans solely for research purposes with a combined effective 
dose of 1.6 rem. This is below the guideline of 5.0 rem per year allowed for research 
subjects by the NIH Radiation Safety Committee. 
 
14.5 
Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
drug administration plan, research objectives, and follow-up of this trial.  The patient will be 
provided a study chart and an IRB-approved consent for review and signature, and his/her 
questions will be answered.  After a decision is made to enroll into the study, a signature will be 
obtained from the patient.  The original signed consent goes to Medical Records; a copy will be 
placed in the research record. Patients will not be consented by telephone. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary, and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason, and because there is a prospect of direct benefit from 


61 
 
research participation, all subjects ≥ age 18 at the NCI only will be offered the opportunity to 
fill in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
 
 
14.5.1 Patient Advocate 
The patients’ rights representative is available to patients receiving treatment on this 
protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical 
Research Center, Room 1-3521, on the Bethesda NIH campus.  Patients enrolled at other 
sites will be given information regarding their local patient advocate.  Patients will be 
informed that they can contact the study PI or RN at any time with questions about their 
medical care, and that the patients’ rights representative is also available to answer non-
medical questions about the study.  
 
 
 


62 
 
REFERENCES 
 
1. 
Wang JC. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev 
Mol Cell Biol. 2002;3(6):430-40. 
2. 
Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 
2006;6(10):789-802. 
3. 
Hoki Y, Fujimori A, Pommier Y. Differential cytotoxicity of clinically important 
camptothecin derivatives in P-glycoprotein-overexpressing cell lines. Cancer Chemother 
Pharmacol. 1997;40(5):433-8. 
4. 
Antony S, Kohlhagen G, Agama K, Jayaraman M, Cao S, Durrani FA, et al. Cellular 
topoisomerase I inhibition and antiproliferative activity by MJ-III-65 (NSC 706744), an 
indenoisoquinoline topoisomerase I poison. Mol Pharmacol. 2005;67(2):523-30. 
5. 
Morrell A, Jayaraman M, Nagarajan M, Fox BM, Meckley MR, Ioanoviciu A, et al. 
Evaluation of indenoisoquinoline topoisomerase I inhibitors using a hollow fiber assay. 
Bioorganic & Medicinal Chemistry Letters. 2006;16(16):4395-9. 
6. 
Antony S, Jayaraman M, Laco G, Kohlhagen G, Kohn KW, Cushman M, et al. 
Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline 
MJ-III-65 (NSC 706744) and camptothecin: base sequence analysis and activity against 
camptothecin-resistant topoisomerases I. Cancer Res. 2003;63(21):7428-35. 
7. 
Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A. H2AX: the histone 
guardian of the genome. DNA Repair (Amst). 2004;3(8-9):959-67. 
8. 
Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A 
critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. 
Curr Biol. 2000;10(15):886-95. 
9. 
Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded 
breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273(10):5858-
68. 
10. 
Bassing CH, Alt FW. H2AX may function as an anchor to hold broken chromosomal 
DNA ends in close proximity. Cell Cycle. 2004;3(2):149-53. 
11. 
Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, 
Sedelnikova OA, et al. Genomic instability in mice lacking histone H2AX. Science. 
2002;296(5569):922-7. 
12. 
Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K, Bonner W. Histone H2A 
variants H2AX and H2AZ. Current opinion in genetics & development. 2002;12(2):162-9. 
13. 
Kinders RJ, Hollingshead M, Lawrence S, Ji J, Tabb B, Bonner WM, et al. 
Development of a Validated Immunofluorescence Assay for Î³H2AX as a Pharmacodynamic 
Marker of Topoisomerase I Inhibitor Activity. Clinical Cancer Research. 2010;16(22):5447-57. 
14. 
Apostolaki S, Perraki M, Pallis A, Bozionelou V, Agelaki S, Kanellou P, et al. 
Circulating HER2 mRNA-positive cells in the peripheral blood of patients with stage I and II 
breast cancer after the administration of adjuvant chemotherapy: evaluation of their clinical 
relevance. Ann Oncol. 2007;18(5):851-8. 
15. 
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. 
Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J 
Med. 2004;351(8):781-91. 
16. 
Danila DC, Heller G, Gignac GA, Gonzalez-Espinoza R, Anand A, Tanaka E, et al. 
Circulating Tumor Cell Number and Prognosis in Progressive Castration-Resistant Prostate 


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Cancer. Clin Cancer Res. 2007;13(23):7053-8. 
17. 
Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, et al. 
Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer 
patients predict progression-free and overall survival. Clin Cancer Res. 2006;12(14 Pt 1):4218-
24. 
18. 
Pfister TD, Reinhold WC, Agama K, Gupta S, Khin SA, Kinders RJ, et al. 
Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and 
microarray analysis and correlation with indenoisoquinoline sensitivity. Molecular Cancer 
Therapeutics. 2009;8(7):1878-84. 
19. 
Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, Elliott F, et al. Predictive 
biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS 
trial. J Clin Oncol. 2008;26(16):2690-8. 
20. 
Meng LH, Liao ZY, Pommier Y. Non-camptothecin DNA topoisomerase I inhibitors 
in cancer therapy. Curr Top Med Chem. 2003;3(3):305-20. 
21. 
Kohlhagen G, Paull KD, Cushman M, Nagafuji P, Pommier Y. Protein-linked DNA 
strand breaks induced by NSC 314622, a novel noncamptothecin topoisomerase I poison. Mol 
Pharmacol. 1998;54(1):50-8. 
22. 
Yap TA, Olmos D, Brunetto AT, Tunariu N, Barriuso J, Riisnaes R, et al. Phase I trial 
of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic 
studies. J Clin Oncol. 2011;29(10):1271-9. 
23. 
Srivastava AK, Jaganathan S, Stephen L, Hollingshead MG, Layhee A, Damour E, et 
al. Effect of a Smac Mimetic (TL32711, Birinapant) on the Apoptotic Program and Apoptosis 
Biomarkers Examined with Validated Multiplex Immunoassays Fit for Clinical Use. Clin Cancer 
Res. 2016;22(4):1000-10. 
24. 
Eder JP, Shapiro GI, Appleman LJ, Zhu AX, Miles D, Keer H, et al. A phase I study 
of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2. 
Clin Cancer Res. 2010;16(13):3507-16. 
25. 
Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, et al. 
Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a 
multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol 
Cancer Ther. 2007;6(7):2012-21. 
26. 
Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated 
titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997;89(15):1138-47. 
27. 
Dancey JF, Boris; Rubenstein, Larry. Accelerated Titration designs. Chevret S, 
editor2006. 
28. 
Basilico C, Pennacchietti S, Vigna E, Chiriaco C, Arena S, Bardelli A, et al. 
Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. 
Clin Cancer Res. 2013;19(9):2381-92. 
 
 


64 
 
 
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. 


65 
 
APPENDIX B: CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP Form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways: (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
 


66 
 
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
• The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
• The Coordinating Center must be designated on the title page. 
• Central registration of patients is required.  The procedures for registration must be stated 
in the protocol. 
• Data collection forms should be of a common format.  Sample forms should be submitted 
with the protocol.  The frequency and timing of data submission forms to the 
Coordinating Center should be stated. 
• Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
• Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.  
 
Agent Ordering 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
investigational agents directly from CTEP (See Section 8).  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been forwarded 
by the Coordinating Center to the CTEP PIO.  
 


67 
 
APPENDIX C: PD/PK COLLECTION WORKSHEETS AT THE NCI 
 
                 RESEARCH URINE SAMPLE COLLECTION SHEET: CYCLE 1 DAY 1 
CTEP Protocol 10002 
Site: 
 
Page ----------------------------
for sample pick-up  
Lab phone: 301-451-1169 
Research Nurse: Murielle Hogu, RN 
Dose level: 
LMP744   Dose: 
 
Phone: (240) 858-3335        Pager: 
Patient ID: 
 
PI: Alice Chen, MD       
Phone: (240) 781-3274   
PLEASE ENTER DATE, TIME, and VOLUME OF EACH VOID FOR 24 HOURS POST DRUG ADMINISTRATION 
KEEP SAMPLES REFRIGERATED UNTIL PICKED UP 
Date 
Time 
Volume of Void 
Aliquot Obtained 
(Please check box) 
Record comments (i.e., if collection missed), and sign each time 
you collect a sample 
Pre-Drug Administration (SAMPLE #100) 
 
 
 
 
 
Administer LMP744 IV, Start Time: 
DAY 1 urine for the first 8 hours after start of infusion (0-8 hours), refrigerate.  Send entire urine collection for PK analysis (SAMPLE #101) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 DAY 1 urine for the next 8 hours after start of infusion (8-16 hours), refrigerate.  Send entire urine collection for PK analysis (SAMPLE #102)  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
  
 
 
 
  
  
 
 
 
  
 
 
 
 
 
Date 
Time 
Volume of Void 
Aliquot Obtained 
Record comments (i.e., if collection missed), and sign each time 


68 
 
(Please check box) 
you collect a sample 
DAY 1 urine for the last 8 hours after start of infusion (16-24 hours), refrigerate.  Send entire urine collection for PK analysis (SAMPLE #103)   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End 24-hour Urine Collection Time: 
Please Send a Copy of this sheet with the last specimen. 
 
 
 
 


69 
 
Date:  
             PK/PD BLOOD SAMPLE COLLECTION SHEET: Cycle 1 Days 1-5 
CTEP Protocol 10002 
Ht:  
Page -------------------------
for Sample Pick-up 
Lab phone: 301-451-1169 
Research Nurse: Murielle Hogu, RN 
Dose level: 
Dose LMP744: 
Wt:   
Phone: (240) 858-3335        Pager: 
Patient ID: 
BSA:   
PI: Alice Chen, MD       
*****PK SAMPLES GO ON ICE****** 
 Phone: (240) 781-3274    
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual 
Time 
Record comments (i.e., if collection missed), and 
sign each time you collect a sample 
Day 1 
Prior to LMP744 
administration 
PK 200 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
  
Day 1 
Prior to LMP744 
administration 
 
PD 400 Streck tube, 1 x 7.5 mL 
Label tubes: drug, draw date and time  
Room temperature 
 
 
 
Administer LMP744 IV, Start Time: 
Day 1 
2 min before end 
of infusion 
PK 201 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
Day 1 
15 min after 
infusion 
PK 202 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
Day 1 
30 min after 
infusion 
PK 203 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
Day 1 
1 hour after end 
of infusion 
PK 204 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
  
  
Day 1 
2 hours after 
end of infusion 
PK 205 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
  
Day 1 
4 hours after 
end of infusion 
PK 206 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
  
  
  
Day 1 
6 hours after 
end of infusion 
PK 207 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
  
  
Continued next page 


70 
 
Day 
Time 
Instructions 
Ideal Time 
Actual 
Time 
Record comments (i.e., if collection missed), and 
sign each time you collect a sample 
Day 2 
Prior to infusion 
PK 208 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
24 hr after start 
of D1 Infusion 
 
 
Day 2 
2 min before end 
of infusion 
PK 209 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
 
 
 
 
 
 
 
 
 
Day 3 
Prior to infusion 
PK 210 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
24 hr after start 
of D2 Infusion 
Day 3 
2 min before end 
of infusion 
PK 211 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
 
 
 
Day 3 
Within 2-4 hours 
after the start of 
LMP744 infusion 
PD 401 Streck tube, 1 x 7.5 mL 
Label tubes: drug, draw date and time  
Room temperature 
 
 
 
 
 
 
Day 4 
Prior to infusion 
PK 212 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
24 hr after start 
of D3 Infusion 
Day 4 
2 min before end 
of infusion 
PK 213 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
 
 
 
 
Day 5 
Prior to infusion 
PK 214 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
24 hr after start 
of D4 Infusion 
 
 
Day 5 
2 min before end 
of infusion 
PK 215 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
 
 
 
 
 
 
 
 
 
 


71 
 
 
Date:  
     PK/PD BLOOD SAMPLE COLLECTION SHEET: Cycle 1 Day 8 
CTEP Protocol 10002 
Ht:  
Page -------------------------
for Sample Pick-up 
Lab phone: 301-451-1169 
Research Nurse: Murielle Hogu, RN 
Dose level: 
Dose LMP744: 
Wt:   
Phone: (240) 858-3335        Pager: 
Patient ID: 
BSA:   
PI: Alice Chen, MD       
*****PK SAMPLES GO ON ICE****** 
 Phone: (240) 781-3274   
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual 
Time 
Record comments (i.e., if collection missed), and 
sign each time you collect a sample 
Day 8 
Prior to LMP744 
infusion 
PK 216 K2-EDTA 3 mL 
Label tube: drug, draw date and time 
PLACE ON ICE 
72 hr after start 
of D5 Infusion 
 
 
 
 
 
 
Date:  
PK/PD BLOOD SAMPLE COLLECTION SHEET:  
Day 1 of each cycle/at progression per PI 
CTEP Protocol 10002 
Ht:  
Page -----------------------------
for Sample Pick-up 
Lab phone: 301-451-1169 
Research Nurse: Murielle Hogu, RN 
Dose level: 
Dose LMP744: 
Wt:   
Phone: (240) 858-3335        Pager: 
Patient ID: 
BSA:   
PI: Alice Chen, MD       
    Phone: (240) 781-3274   
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal Time 
Actual 
Time 
Record comments (i.e., if collection missed), and sign 
each time you collect a sample 
Day 1 
Prior to LMP744 
administration 
 
PD 40X Streck tube, 1 x 7.5 mL 
Label tubes: drug, draw date and time  
Room temperature 
 
 
 
 
 


72 
 
APPENDIX D: PROCEDURE FOR SAMPLES FOR PHARMACODYNAMIC STUDIES 
COLLECTED AT PARTICIPATING SITES  
 
Isolation of CTCs  
Prior to CTC collection, each participating outside site should e-mail a request for specimen 
collection and shipping materials from NCI_PD_Support@mail.nih.gov.  Allow at least six 
business days for receipt of the blood shipment containers; a confirmation e-mail with the 
expected shipping date will be sent.  
 
Blood will be collected aseptically by venipuncture or from a venous port into one 7.5 mL 
CellSave preservative tube (catalog number 413988) or one 10 mL Streck Cell-Free DNA BCT 
blood collection tube (catalog number 218962); the collected blood samples are stable for up to 
48 hours at room temperature (15˚C to 30˚C) prior to processing.   
 
Samples from participating sites will be sent to: 
 
Attention: Dan Danner 
NCI-F/FNLCR 
1073 Beasley Street, Building 1073 
Fort Detrick 
Frederick, MD 21701 
Phone: 301-846-5748 
 
E-mail NCI_PD_Support@mail.nih.gov prior to shipping with expected arrival date/time and a 
description of contents.  All shipments should include a description of contents on the outside 
label/shipping slip, and a detailed packing slip should be included with the samples.  Because of 
the 48-hour window of CTC sample stability, CTC samples should be shipped to arrive when 
specified below: 
 
Collection Day 
Day/time samples must arrive at PADIS 
Monday 
Wednesday (early morning) 
Tuesday 
Thursday (early morning) 
Wednesday 
Friday (early morning) 
Thursday 
Friday (early morning) 
Saturday 
Monday (early morning) 
Sunday 
Tuesday (early morning) 
CTC samples may not be collected on Fridays. 

ICF_001.pdf: 
 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
Version Date: 1/6/2023 
Page 1 of 15 
CC ICF template v. 09.27.19 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
PRINCIPAL INVESTIGATOR:  Alice Chen, M.D. 
STUDY TITLE: A Phase I Study of Indenoisoquinoline LMP744 in Adults With Relapsed Solid Tumors and 
Lymphomas  
STUDY SITE: NIH Clinical Center  
Cohort: Patients 
Consent Version:  1/6/2023 
 
 
WHO DO YOU CONTACT ABOUT THIS STUDY?  
Alice Chen, Principal Investigator: 240-781-3274 
 
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).  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.  Taking part in research at the NIH is your 
choice. 
If the individual being asked to participate in this research study is not able to give consent for themselves, you, 
as the Legally Authorized Representative, will be their decision-maker and you are being asked to give permission 
for this person to be in this study.  For the remainder of this document, the term “you” refers to you as the decision-
maker and/or the individual being asked to participate in this research. 
 
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 study involves your choosing to take part in a clinical research study.  You are being asked to take part in 
this study because standard therapies have not been effective for the type of cancer you have.  We are studying 
an experimental drug in this trial, LMP744, which damages DNA, resulting in cell death.  
This is the first time that LMP744 is being given to humans.  LMP744 is an investigational drug and is not 
approved by the Food and Drug Administration (FDA).  The purpose of this study is to test the safety of LMP744 
and find out the dose of the drug that can be safely given to humans.  We are trying to understand how this drug 
works, how your body handles the drug, and what side effects occur.  We may also ask you to give blood and 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
Version Date: 1/6/2023 
Page 2 of 15 
CC ICF template v. 09.27.19 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
tumor biopsy samples to help us learn about how LMP744 works in your body and in your tumor.   
Up to 53 patients will take part in this study at several centers across the United States.  
 
WHAT IS THE USUAL APPROACH TO MY CANCER? 
You are being asked to take part in this research study because standard medical treatments such as chemotherapy, 
surgery, and/or radiotherapy have not been very effective for the type of advanced cancer that you have.  
 
WHAT ARE MY OTHER CHOICES IF I DO NOT TAKE PART IN THIS STUDY? 
Instead of being in this study, you have these options: 
• Getting other therapies that, although might not improve survival, may have other benefits, such as 
delaying disease progression. 
• Taking part in another study. 
• Getting no treatment.  
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite 
problems, and other problems caused by cancer.  It does not treat the cancer directly, but instead tries to 
improve how you feel.  Comfort care tries to keep you as active and comfortable as possible. 
 
WHAT ARE THE STUDY GROUPS? 
All of the participants in the study will receive the study drug LMP744.  Different doses of LMP744 will be 
given to one or more study participants.  The first several study participants will receive the lowest doses.  If the 
drug does not cause serious side effects, it will be given to other study participants at higher doses.  The doses 
will continue to increase until side effects occur that require the dose to be lowered.  Once the appropriate dose 
is identified, several more patients will be treated at that dose. 
 
HOW LONG WILL I BE IN THIS STUDY? 
During the study, you will take LMP744 through a central line, a tube placed into your vein.  If you already 
have a central line, it will be used to give you LMP744.  If you do not already have a central line, a temporary 
one will be placed for as long as you are in the study.  Treatment will take 60 minutes and will be given once a 
day for 5 days.  LMP744 will be given in cycles.  Each cycle is 28 days long, so you will be given LMP744 for 
5 days followed by 23 days without drug.  
You will continue to receive LMP744 for as long as you are tolerating it and your cancer is either stable or 
getting better.   
 
Your doctor will continue to watch you for side effects and follow your condition for 30 days after you finish 
the study, or until any drug-related side effects you may have had have stabilized or resolved.   
 


 
PATIENT IDENTIFICATION 
Consent to Participate in a Clinical Research Study 
NIH-2977 (4-17) 
File in Section 4: Protocol Consent (1) 
Version Date: 1/6/2023 
Page 3 of 15 
CC ICF template v. 09.27.19 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
WHAT EXTRA TESTS AND PROCEDURES WILL I HAVE IF I TAKE PART IN THIS STUDY? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your cancer.  
However, there are some extra tests and procedures that you may need to have if you take part in this study that 
are not part of the usual approach for your type of cancer.   
 
You may have the following extra tests and procedures during the study:  
• Central line insertion 
o Prior to starting treatment, you may need to have a “tunneled” catheter inserted.  This type of 
catheter is a thin, long tube made of flexible, silicone rubber that is surgically inserted into one of 
the main blood vessels leading to your heart.  One end of the catheter is inserted through a small 
incision into the main blood vessel leading into your heart.  The other end of the catheter may be 
tunneled under your skin and comes out through your skin through a second small incision. 
o Your doctor or nurse will explain the procedure in detail, and you will be asked to sign a separate 
consent.  Before you go home, you will be given instructions on how to care for the catheter. 
• Imaging tests 
o CT scans or other imaging tests that detect your tumor will be done every 2 cycles (about every 
8 weeks) while you are receiving treatment 
o Imaging may be done every 3 cycles if you have been on study for more than 1 year or every 
4 cycles if on study for more than 3 years 
• Research blood samples  
o Blood samples will be collected before you receive study drug and then at several times during 
cycle 1 only so that we can measure how your body handles LMP744.  The total blood for all 
these tests will be about 2 tablespoons (about 30 mL) 
o Blood samples will be collected to assess any changes in tumor DNA in your blood.  Samples 
will be collected before you take drug, on the first day of every cycle for as long as you are on 
study, and if your cancer progresses.  Each blood collection is less than 2 tablespoons. 
o Optional blood samples will be collected to find out the effects of the drug on any tumor cells in 
your blood.  Samples will be collected before you first take drug, on day 3 of cycle 1, on the first 
day of every cycle for as long as you are on study, and when you come off study.  Each blood 
collection is about 2 teaspoons 
• An EKG (electrocardiogram) and ECHO (echocardiogram) 
o An EKG and ECHO to check your heart will be done before the study and before cycles 3 and 5, 
and may be repeated while you are receiving treatment if the study doctor thinks it is needed to 
check for signs of possible damage to your heart  
• A urine or serum pregnancy test for women of childbearing potential is required prior to every cycle 
• Tumor biopsies will be required before you receive study drug and again on day 2 of cycle 1 after drug 
administration.  Biopsies are a very important part of this trial and are done for research purposes 
o Willingness to undergo tumor biopsies will be required for taking part.  After the initial biopsy, if 
you decide not to have further biopsies, you will still receive LMP744 and have other tests that 
are part of the study 
o You will be asked to sign a separate consent form for each optional biopsy procedure 
 
Tumor biopsies are only collected by trained personnel.  Biopsies are collected using a small needle 
under imaging guidance (CT, MRI, or ultrasound as deemed appropriate by the interventional 
radiologist performing the biopsy).  Imaging helps the specialized radiologist know that the needle has 


 
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been placed into the tumor mass.  If the interventional radiologist recommends MRI imaging, you may 
receive gadolinium, a contrast agent, through an intravenous (IV) catheter (small tube).  It is not known 
if MRI with contrast is completely safe for a developing fetus.  Therefore, all women of childbearing 
potential will have a pregnancy test performed no more than 24 hours before each MRI scan with 
contrast.  The scan will not be done if the pregnancy test is positive.  
 
Typical risks of biopsy collection include, but are not limited to, bleeding, infection, pain, and scarring.  
If you experience any complications from the biopsy, medical care will be offered to you.  You will be 
counseled in more detail about biopsies, and you will be asked to sign a separate consent form that will 
describe the procedures and risks at that time.  Your safety is the most important thing at all times.  If 
upon attempting the first biopsy, no tissue can be obtained or it has caused you harm, further biopsies 
will not be done.  After you are enrolled in this study, if for any reason the biopsies cannot be done 
safely, you may still receive the study drugs but the biopsies will not be done. 
 
You will be provided with a study chart that shows when you will need to have these tests and procedures done.  
Neither you nor your health care plan/insurance carrier will be billed for these tests.   
 
WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
You may have side effects while on the study.  Everyone taking part in the study will be watched carefully for 
any side effects.  But doctors do not know all the side effects that may happen when taking LMP744 as this 
drug has never been given to humans.  We do not know if taking LMP744 will cause any other medications you 
may be taking to work differently.  It is very important that you tell a member of the research team before 
starting any new drugs, over-the-counter medications, or alternative therapies.   
 
If you choose to take part in this study, there is a risk that the LMP744 may not be as good as the usual approach 
for your cancer or condition at shrinking or stabilizing your cancer. 
 
You also may have the following discomforts: 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies. 
 
The LMP744 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 test your blood and will let you know if changes occur that may affect 
your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important things to know about side effects: 
• The study doctors do not know who will or will not have side effects. 


 
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• Some side effects may go away soon, some may last a long time, and some may never go away. 
• Some side effects may make it hard for you to have children. 
• Some side effects may be mild.  Other side effects may be very serious and even result in death. 
You can ask your study doctor questions about side effects at any time.  Here are important ways to make side 
effects less of a problem: 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see if it is a side 
effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects doctors know about.  Keep in mind 
that there might be other side effects doctors do not yet know about.  If important new side effects are found, 
the study doctor will discuss these with you. 
 
Let your study doctor know of any questions you have about possible side effects.  You can ask your 
study doctor questions about side effects at any time. 
 
POSSIBLE, SOME MAY BE SERIOUS 
 
• Anemia which may cause tiredness, or may require blood transfusion 
• Infection, especially when white blood cell count is low 
• Nausea, vomiting 
• Death  
• Bruising, bleeding 
• Increased liver enzymes (alanine aminotransferase, aspartate aminotransferase, and/or 
GGT) 
 
Reproductive risks:  
The drug used in this study (LMP744) could be very damaging to an unborn baby.  You should not get pregnant, 
breastfeed, or father a baby while in this study.  If you are a woman who can become pregnant, or are the 
partner of a woman who can become pregnant, you will need to practice an effective form of birth control 
before starting study treatment, during study treatment, and for 4 months after you finish study treatment.  
Check with the study doctor about what types of birth control, or pregnancy prevention, to use while in this 
study.  If you think that you or your partner is pregnant, you should tell your study doctor or nurse at once.   
 
Potential Risks Related to Research-Related Imaging Studies:  
During your participation in this research study, you may be exposed to radiation from CT scans each year.  The 
amount of radiation exposure from these procedures is equal to approximately 1.6 rem. A rem is a unit of absorbed 
radiation.   


 
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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.”  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 roughly the same amount of radiation as 5 years’ worth 
of background radiation.  Most of the time, this amount of extra radiation is not harmful to you.  However, 
scientists believe that being exposed to too much radiation can cause harmful side effects.  This could include 
getting a new cancer.  We estimate that this could happen in about 1 out of every 1000 people who get a very 
large amount of extra radiation. 
Contrast agent: 
Some types of cancer require a contrast agent to be used for imaging studies.  There is a chance of developing an 
allergic reaction from the contrast material, which may cause symptoms ranging from mild itching or a rash to 
severe difficulty breathing, shock or rarely, death.  The contrast material may also cause kidney problems.  The 
study doctors will do a blood test prior to the test to confirm that it is safe you to receive the contrast. 
For IV contrast: You may feel discomfort when the contrast material is injected. You may feel warm, flushed, get 
a metallic taste in your mouth or, rarely, may make you vomit or feel sick to your stomach.   
For oral contrast:  You may experience vomiting, nausea, cramping, bloating, constipation or diarrhea after 
drinking the contrast. 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with pain and 
swelling.   
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and usually go away 
quickly.  Mild symptoms may include coldness in the arm during the injection, a metallic taste, headache, and 
nausea.  In an extremely small number, fewer than one in 300,000 people, more severe symptoms have been 
reported including shortness of breath, wheezing, hives, and lowering of blood pressure. You should not receive 
gadolinium if you previously had an allergic reaction to it.  You will be asked about such allergic reactions before 
gadolinium is given.    
People with kidney disease are at risk for a serious reaction to gadolinium contrast called “nephrogenic systemic 
fibrosis (NSF)”.  This condition always involves the skin and can also involve the muscles, joints and internal 
organs.  NSF has resulted in a very small number of deaths.  A blood test of your kidney function may be done 
within the month before an MRI scan with gadolinium contrast. You will not receive gadolinium for a research 
MRI scan if your kidney function is below the safe level.  
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a safety alert that 
indicates small amounts of gadolinium may remain in the body for months to years.  The long-term effects of the 
retained gadolinium are unknown.  Some types of gadolinium contrast drugs are less likely to remain in the body 
than others.  In this study, we will use the gadolinium contrast drugs that are less likely to remain in the body, 
whenever possible. We will also give you additional information called a “Medication Guide.”  Upon request, we 
will give you individual information about retained gadolinium we see on your studies. 
 
Central line insertion: 
Central catheter placement is very common and is generally well tolerated.  The most common risk is infection 
which is treated with antibiotics or removal of the catheter.  Additional risks include, clots forming inside or along 


 
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the outside of the catheter which can break off and travel to the veins near your neck, face, chest, arms or lungs 
(pulmonary embolism).  If you develop blood clots, your doctor will give you the appropriate treatment which 
may include blood thinners.  Uncommon side effects include swelling of the face and arm and/or lung collapse.  
If the lung collapses, it may be necessary to place a tube between the ribs to allow the lung to re-expand.  Rarely 
the catheter can break or air could enter the catheter and travel to the veins near your neck, face, chest, arms or 
lungs. 
 
WHAT POSSIBLE BENEFITS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
This study is unlikely to help you.  The knowledge gained from this study may help others in the future who 
have cancer.   
 
CAN I STOP TAKING PART IN THIS STUDY? 
Yes.  You can decide to stop at any time.  If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop taking the study drug safely. 
 
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.  However, according to FDA guidelines, information collected on you up to that 
point may still be provided to the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute 
(NCI) or designated representatives.  If you withdraw your consent and leave the trial, any samples of yours that 
have been obtained for the study and stored at the NCI can be destroyed upon request.  However, any samples 
and data generated from the samples that have already been distributed to other researchers or placed in the 
research databases cannot be recalled and destroyed. 
 
The study doctor will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If your disease comes back during treatment 
• If you have side effects from the treatment that your doctor thinks are too severe 
• If new information shows that another treatment would be better for you 
• If you become pregnant 
• If the study is stopped by the sponsor, the IRB (people who review the research to protect the people 
taking part in the study), or FDA. 
 
STUDY CHART 
Day 
What to do and what will happen to you 
Before 
starting 
study drug 
• Check in at the Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by 
a Health Care Provider 
• Get routine blood and urine tests 
• Pregnancy test for women who are able to become pregnant 


 
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Day 
What to do and what will happen to you 
• CT or MRI scan will be done 
• Research blood and urine samples will be taken 
• Tumor biopsy will be taken  
• EKG and ECHO will be done to check your heart 
Cycle 1, 
Day 1 
• Check in at Outpatient Clinic 
• Get routine blood and urine tests 
• Receive the first dose of LMP744 through a vein 
• Blood draws for research will be obtained at multiple times 
Cycle 1, 
Days 2-5 
• Check in at Outpatient Clinic 
• Continue to receive LMP744 through a vein 
• Blood draws for research will be obtained at multiple times 
• Tumor biopsy will be taken on Day 2  
Cycle 1, 
Day 8 
• Check in at Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by 
a Health Care Provider 
• Get routine blood and urine tests 
• Blood draws for research will be obtained 
Cycle 1, 
Day 15 
• Check in at Outpatient Clinic 
• Get routine blood and urine tests 
Cycle 2, 
Days 1-5  
• Check in at Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by 
a Health Care Provider on day 1 
• Get routine blood and urine tests 
• Blood draws for research may be obtained on day 1 
• Receive LMP744 through a vein on days 1-5  
Cycle 2, 
Day 15 
• Check in at Outpatient Clinic 
• Get routine blood and urine tests 
• EKG and ECHO will be done to check your heart before cycle 3 and again 
before cycle 5 
Cycle 3 
and 
onwards, 
Day 1 
• Check in at Outpatient Clinic 
• Have a history taken of how you feel and undergo a physical examination by 
a Health Care Provider 
• Get routine blood and urine tests 
• Blood draws for research may be obtained 
• Receive LMP744 through a vein 
• CT or MRI scans to determine how your tumor is responding to the drug 
every 2 cycles (less often if you have been on study for more than one year) 
Cycle 3 
and 
• Receive LMP744 through a vein 


 
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Day 
What to do and what will happen to you 
onwards, 
Days 2-5 
Cycle 3 
only, Day 
15 
• Check in at Outpatient Clinic 
• Get routine blood and urine tests 
After 
finishing 
treatment 
• You will be followed for 30 days after your last dose of drug is administered  
• Blood draws for research may be obtained  
• Between Day 27 and 30 we will contact you by phone to check on you 
 
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 
 
WILL YOUR SPECIMENS OR DATA BE SHARED FOR USE IN OTHER RESEARCH STUDIES? 
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 
 


 
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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.  
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. 
 
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.  
 
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. 
 
No NIH investigator involved in this study receives payments or other benefits from any company whose drug, 
product or device is being tested. 


 
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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?  
Your privacy is very important to us and the researchers will make every effort to protect it.  The study doctors 
have a privacy permit to help protect your records if there is a court case.  However, some of your medical 
information may be given out if required by law.  For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis.  However, the researchers will do their best to make sure that any 
information that is released will not identify you.  Some of your health information, such as your response to 
cancer treatment, results of study tests, and medicines you took, will be kept in a central database for research.  
Your name or contact information will not be put in the database.  If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be used. 
 
In addition to the above which is handled by the study sponsor (the Cancer Therapy Evaluation Program or 
CTEP), we may put your research data in a large database for broad sharing with the research community.  
These databases are commonly called data repositories.  These data repositories might or might not be located 
at the NIH.  The information in this database could include but is not limited to genetic information, ethnicity 
and sex.  If your individual research data is placed in one of these repositories, it will not be labeled with your 
name or other information that could be used to easily identify you, and only qualified researchers will be able 
to look at your data. These researchers must receive prior approval from individuals or committees to access 
the data. 
 
There are organizations that may inspect your records.  These organizations are required to make sure your 
information is kept private, unless required by law to provide information.  Some of these organizations are: 
• The study sponsor.  
• The Institutional Review Board, IRB, a group of people who review the research with the goal of 
protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S., and similar ones if 
other countries are involved in the study. 
 
Your study records also will be stored for future use.  However, your name and other personal information will 
not be used.  Some types of future research may include looking at your records and those of other patients to see 
who had side effects across many studies or comparing new study data with older study data.  However, we don’t 
know what research may be done in the future using your information.  This means that: 
• You will not be asked if you agree to take part in the specific future research studies using your health 
information.   
• You and your study doctor will not be told when or what type of research will be done. 
• You will not get reports or other information about any research that is done using your information. 


 
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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 for auditing 
or program evaluation internally by the NIH; or  
2. is required to be disclosed by Federal, State, or local laws, for example, when information must be 
disclosed to meet the legal requirements of the federal Food and Drug Administration (FDA);  
3. is for other research; 
4. is disclosed with your consent.  
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research.  
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or others 
including, for example, child abuse and neglect, and by signing below you consent to those disclosures. 
Other permissions for release may be made by signing NIH forms, such as the Notice and 
Acknowledgement of Information Practices consent. 
Privacy Act  
The Federal Privacy Act generally protects the confidentiality of your NIH medical information that we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act protections 
differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act allows release of 
information from your record without your permission, for example, if it is requested by Congress. 
Information may also be released for certain research purposes with due consideration and protection, to 
those engaged by the agency for research purposes, to certain federal and state agencies, for HIV partner 
notification, for infectious disease or abuse or neglect reporting,  to tumor registries, for quality assessment 
and medical audits, or when the NIH is involved in a lawsuit.  However, NIH will only release information 
from your medical record if it is permitted by both the Certificate of Confidentiality and the Privacy Act. 
 
POLICY REGARDING RESEARCH-RELATED INJURIES   
The NIH Clinical Center will provide short-term medical care for any injury resulting from your participation in 
research here. In general, no long-term medical care or financial compensation for research-related injuries will 
be provided by the NIH, the NIH Clinical Center, or the Federal Government. However, you have the right to 
pursue legal remedy if you believe that your injury justifies such action. 
 
PROBLEMS OR QUESTIONS 
If you have any problems or questions about this study, or about your rights as a research participant, or about 
any research-related injury, contact the Principal Investigator, Dr. Alice Chen, chenali@mail.nih.gov, (240) 781-


 
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3274. You may also call the NIH Clinical Center Patient Representative at 301-496-2626, or the NIH Office of 
IRB Operations at 301-402-3713, if you have a research-related complaint or concern. 
 
CONSENT DOCUMENT  
Please keep a copy of this document in case you want to read it again. 
 


 
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY 
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study. 
 
 
 
 
 
Signature of Research Participant 
 
Print Name of Research Participant 
 
Date 
 
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study. 
 
 
 
 
 
Signature of LAR 
 
Print Name of LAR 
 
Date 
 
Investigator: 
 
 
 
 
 
Signature of Investigator 
 
Print Name of Investigator 
 
Date 
 
 


 
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Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation. 
 
Witness: 
 
 
 
 
 
Signature of Witness* 
 
Print Name of Witness 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER: 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness. 
 
 
 
 
 
 
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated 
the administration of informed consent but did not serve as a witness. The name or ID code of the person  
providing interpretive support is: 
 
.