Extending precision medicine beyond mutations: 🎯🎯 Targeted Radiopharmaceuticals and ETCTN trials

Aman Chauhan, MDAssistant Professor of MedicineDivision of Medical OncologyDirector of NET Theranostics

DisclosuresResearch Support/Grants:

BMS

Clovis

Lexicon

EMD Serono

Nanopharmaceuticals

ECS Progastrin

Advisor:

Lexicon

Ipsen

Theranostic

TheranosticTargeted radiopharmaceutical: small amount of radioactive material linked to a cell-targeting agent for the treatment of cancer1

Lutetium 177 (177Lu)dotatate, a radiolabeled somatostatin analog approved for the treatment of midgut carcinoid tumors2

177Lu-PSMA-617, a radiolabeled prostate-specific membrane antigen-binding (PSMA) dipeptide in Phase III for mCRPC3

GrzmilM et al. An Overview of Targeted Radiotherapy. In: J. S. Lewis, A. D. Windhorst and B. M. ZeglisRadiopharmaceutical Chemistry. Springer International Publishing, Cham. 2019:pp85–100;2. LutatheraPrescribing Information. July 2018.Advanced Accelerator Applications, Inc.;3. ClinicalTrials.gov. https://clinicaltrials.gov. Accessed May 3, 2020

Multiple new targets and radionuclides in development in various cancers

Baum RP. ICPO Foundation Symposium, 2019. Breast Ca

Pancreatic CaColorectal Ca

Neuroendocrine Neoplasms

Chauhan et. al: Diagnosis and Management of Large Cell Neuroendocrine Carcinoma.Springer Textbook (In press)

Incidence of NETS on a rise

Year # of NET

KY Census Cases/100K

cases

x 100,000

1995 146 38.87 3.76

1996 165 39.20 4.21

1997 177 39.53 4.48

1998 212 39.85 5.32

1999 234 40.18 5.82

2000 242 40.42 5.99

2001 259 40.68 6.37

2002 302 40.90 7.38

2003 286 41.17 6.95

2004 306 41.46 7.38

2005 309 41.83 7.39

2006 351 42.19 8.32

2007 405 42.57 9.51

2008 418 42.90 9.74

2009 434 43.17 10.05

2010 493 43.39 11.36

2011 433 43.70 9.91

2012 469 43.83 10.70

Site Prevalence

Lung 30.6

Small Intestine 16.82

Rectum/Anus 11.35

Colon 9.71

Pancreas 5.5

Others 12.91

Unknown 7.61

Chauhan et.al Oncotarget2018

Prevalence of Various Solid Tumors in the United States

Chauhan et. al JAMA Oncol 2019

NETTER-1 Phase III RCT: Lu 177 DOTATATE PRRT

Strosberg et. al NEJM 2018

NETTER-1 Phase III RCT: Lu 177 DOTATATE PRRT

Strosberg et. al NEJM 2018

Markey Cancer Center NET Clinic

PRRT-Current Advances and Challenges

FDA approval of Lu-177 DOTATATE b on improved PFS (NETTER-1)

Short Term Challenges

Long Term Challenges

PRRT is now mainstream

Only 18% ORR Improve PFS/OS/QoL

Non GEPNET CohortsPRRT Sequencing

Long term toxicity mitigation

PRRT Refractory-Resistant Disease

PRRT ROADMAP

First FDA approved PRRT agent 2018Lu-177 DOTATATE

Lu-177 DOTATOCAlpha Emitters

Novel PRRT Agents

Lu-177 DOTATATE+TriapineLu-177 DOTATATE+Olaparib

PRRT+ Agent X?

Combination Trials

Improved ORR, mPFS, OS, QoLLimiting Systemic toxicityLimiting Financial Toxicity

Improved Efficacy and Lower Toxicity

Combination Trials

Improved Efficacy and Lower Toxicity

Investigator Initiated Clinical TrialsI. Phase I: Investigator Initiated, multi center

Triapine+PRRT in NETsII. Phase I: Investigator Initiated, multi center

M3814+PRRT in NETsIII. Phase II: Investigator Initiated, single center

Telotristat+PRRT in NETsIV. Phase II: Investigator Initiated, single center

Nivolumab+ Rucaparib in SCLC

Triapine® is a ribonucleotide reductase (RNR) inhibitor.

RNR is an enzyme that is responsible for the reduction of ribonucleotides to deoxyribonucleotides in the biosynthesis of deoxyribonucleic acid (DNA)

This reduction process is a rate-limiting step due to the extremely low levels of deoxyribonucleotides in mammalian cells

RNR potentiates antitumor activity of DNA–damaging agents by inhibiting DNA repair

Triapine (3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone or 3-AP)

Triapine

triapine

Triapine as a radiation sensitizerStudy 8327: A Phase 2 Study of Triapine® (NSC #663249) and Cisplatin in Combination with Pelvic Radiation for Treatment of Stage IB2-IV Cervical Cancer or Stage II-IV Vaginal Cancer

Twenty-four (96%) among 25 patients achieved durable CRs with a median follow-up of 20 months (range 2-35 months)

Twenty-three (96%) of 24 patients had PET/CT scans 3 months post therapy that recorded metabolic activity in the cervix or vagina equal to or less than that of the cardiac blood pool, suggesting metabolic CRs.

The most frequent treatment related AEs were fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities.

Triapine as a radiation sensitizer

Long-term disease control with Triapine-based radiochemotherapy for patients with stage IB2-IIIB cervical cancer.

Kunos and Sheretz reported that the three-year disease-free survival in these patients was 80%, and that the local relapse rate was only 4%

Kunos CA, Sheretz TM. Long-term disease control with Triapine-based radiochemotherapy for patients with stage IB2-IIIB cervical cancer. Front Oncol 2014; 4:1-5.

Triapine + XRT pre-clinical studies

Zeta Chao, MD (University of Kentucky)

Triapine QGP&BON 0Gy vs. 2Gy T1 high molecular weight run

QGP – 0 Gy – T1pDNA-PK

pATM

pATR

β-actin

BON – 0 Gy – T1

pDNA-PK

pATR

β-actin

QGP – 2 Gy – T1

pDNA-PK

pATM

pATR

β-actin

BON – 2 Gy – T1

pDNA-PK

pATR

β-actin

A Phase I Trial of Triapine and Lutetium Lu 177 Dotatate in Combination for Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

NCI CTEP Career Development Award 2019

Study Endpoints

Dose Escalation Schedule

Dose LevelDose*

Triapine Lutetium Lu 177 Dotatate

Level -2 50 mg PO QOD, Days 1-14

200 mCi IV, Day 1

Level -1 50 mg PO QD, Days 1-14

Level 1# 100 mg PO QD, Days 1-14

Level 2 150 mg PO QD, Days 1-14

Level 3 200 mg PO QD, Days 1-14

PO = orally; QOD = every other day; QD = every day; IV = intravenously*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage.#Starting dose.

Primary Objectives

1. To evaluate the safety and to determine the recommended phase 2 dose (RP2D) of Lutetium Lu 177 Dotatate in combination with triapine.

Secondary Objectives

1. To determine the overall response rate (ORR) by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 at 2, 4, 6, and 8 months

2. To measure duration of response (DOR) associated with the combination.

3. To evaluate progression-free survival (PFS), 24-month PFS, and overall survival (OS).

Correlative studies• Measure baseline 68gallium-dotatate biodistribution.

• Evaluate oral triapine plasma pharmacokinetics and corresponding methemoglobin level by venous blood gas proportion.

• Evaluate NETest at baseline and disease progression to correlate result with clinical outcome.

• Describe the tumor molecular profile using whole exome sequencing (WES), as well as RNAseq by the National Clinical Laboratory Network (NCLN) Genomics Lab, and correlate it with treatment outcome.

• Collect plasma for circulating DNA (ctDNA) assessment.

TimelineGrant Approved: 10-2019

Protocol Written: 12-2019

NCI CTEP, CIRB and FDA approval: 4-2020

Study Open for Accrual: 7-2020 (Commendation letter from NCI for rapid trial activation)

Enrolled first 3 patients and closed first dose cohort: 9-2020

ImpactCutting edge treatments available to our patients

We are national lead site

Trial will be opened at OSU, Huntsman Cancer Center, Yale, Moffit Cancer Center, City of Hope

Collaboration with basic Scientists:

Dr Rychahou and Dr Chao (UK) Dr Beumer (Univ of Pittsburg) Markey Phase I group: After treating first ever

Triapine+PRRT patient- Aug 2020

DNA PKi (M3814; Peposertib)• Radiation is a potent inducer of DNA double-strand breaks (DSB)

• The primary repair mechanism of radiation-induced DSBs is the nonhomologous end-joining (NHEJ) pathway, in which the DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role.

• Upregulation of DNA-PK promotes repair of DSBs leading to tumor radio resistance preclinically and clinically.

• M3814 is a selective inhibitor of DNA-PK that targets tumor cell DNA damage repair and survival by blocking NHEJ.

NET pre-clinical experiments in Dr Piotr Rychahou lab

Sept 2018

Irradiation in Dr Izumi Tadahide lab

Successful completion of first set of experiments in Feb 2019

M3814+XRT Clonogenic Assay

NCI CTEP UM1 Sppl. Aman Chauhan 2018; Dr Rychahou lab (UK)

M3814+XRT in vivo data

Chauhan et. al Oral Presentation NANETS (Boston) 2019; Dr Rychahou lab (UK)

A Phase I Trial of M3814 and Lutetium Lu 177 Dotatate in Combination for Well-Differentiated Somatostatin Receptor-Positive Neuroendocrine tumors

NCI CTEP Career Development Award-2020(National PI: Aman Chauhan; Protocol in development)

Telotristat Ethyl

Reduction in Serotonin by inhibition of Tryptophan Hydroxylase

Serotonin and NETsSerotonin promotes NET cell growth

Pts with elevated 24 Hr Urine 5HIAA have poor outcome

Telotristat + Lu 177 dotatate

PI: Aman ChauhanSponsor: Lexicon/Ter-Sera Pharmaceutical

Telotristat + Lu 177 dotatatePrimary Objective: • 20 month Progression Free Survival

Secondary Objective: • Safety Assessment• QoL assessment• Imaging and genomic biomarkers of

response and radiation resistance

Targeted Radiopharmaceuticals

Esthesioneuroblastoma case: Ga68DOTATATE positive; currently on Lu177 DOTATATE treatment.

Acknowledgements Patients Mentors

Dr Lowell Anthony (MCC) Dr Elise Kohn (NCI CTEP) Dr Mark Evers (MCC) Dr Charles Kunos (UK Rad-Onc) Dr Susanne Arnold (MCC) Dr Jill Kolesar (MCC) Dr Heidi Weiss (MCC)

Sponsors NCI CTEP ORIEN Merck KgA (EMD Serono), Nanopharmaceuticals BMS Clovis ECS Progastrin Lexicon

CollaboratorsPiotr RychahouZeta ChaoDerek AllisonRiham EL KhouliGaby GabrielIzumi TadahideJeri ReynoldsDana NapierHeather Heath