PARP Inhibitor With 177Lu-DOTA-Octreotate PRRT in Patients With Neuroendocrine Tumours (PARLuNET)

Phase 1 Trial of PARP Inhibitor Combined With 177Lu-DOTA-Octreotate Peptide Receptor Radionuclide Therapy (PRRT) in Patients With Metastatic NeuroEndocrine Tumor

This phase 1 dose-escalation study is designed to evaluate the safety and tolerability of talazoparib in combination with 177Lu-DOTA-Octreotate peptide receptor radionuclide therapy (PRRT) in patients with metastatic pancreatic or midgut neuroendocrine tumour (NET).

Study Overview

• Status: Recruiting
• Conditions: Neuroendocrine Tumors
• Intervention / Treatment: Drug: Talazoparib

Detailed Description

This phase 1, single arm, single centre study is designed to evaluate the safety and tolerability of talazoparib in combination with 177Lu-DOTA-Octreotate in patients with metastatic NET.

Patients will receive 1 cycle of 177Lu-DOTA-Octreotate alone followed by 3 cycles of 177Lu-DOTA-Octreotate combined with 5 days of talazoparib.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Grace Kong; Phone Number: 85595000; Email: NMResearch@petermac.org
• Study Contact Backup: Name: Research Manager; Phone Number: 8559 6602

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • Peter Maccallum Cancer Centre
      • Contact: MC Research Manager; Phone Number: +61385596602; Email: NMResearch@petermac.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient must be > or equal to18 years of age and must have provided written informed consent.
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
3. Histologically confirmed Grade 2 NET, Ki-67 of 3-20%, from pancreatic or intestinal origin.
4. Patient clinically suitable for PRRT
5. Tumor SSR uptake on GaTate PET/CT higher than liver activity, ≥ modified Krenning 3 score
6. No discordant FDG-avid disease on FDG PET/CT
7. No evidence of significant uncorrected carcinoid heart disease
8. Patients must be willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled assessments

9. Patients must have adequate bone marrow, hepatic and renal function defined as:

   • Haemoglobin ≥100 g/L
   • Absolute neutrophil count ≥1.5x109/L
   • Platelets ≥150 x109/L
   • Total bilirubin ≤1.5 x upper limit of normal (ULN)

   • Aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGPT)

     ≤2.5 x ULN if there is no evidence of liver metastasis or ≤5 x ULN in the presence of liver metastases.

   • Albumin ≥ 30 g/L
   • Adequate renal function: eGFR ≥ 60 ml/min

Exclusion Criteria:

1. Surgery or radiotherapy within <3 weeks of registration. Patients must have recovered from any effects of any major surgery.
2. Any prior exposure to peptide receptor radionuclide therapy (177Lu, 111In or 90Y labelled), PARPi, immunotherapy
3. Uncontrolled intercurrent illness that is likely to impede participation and /or compliance
4. Other malignancies unless curatively treated with no evidence of disease within previous 3-years other than adequately treated non-melanoma skin cancer or melanoma in situ.
5. Previous or current history of myelodysplastic syndrome/acute myeloid leukemia
6. Patients unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with the absorption of the study medication.
7. Use of strong P-gp inhibitors (eg, dronedarone, quinidine, ranolazine, verapamil, ketoconazole, itraconazole), P-gp inducers (eg, rifampin, tipranavir/ritonavir), or BCRP inhibitors (eg, elacridar [GF120918]) should be avoided.
8. Participation in another clinical study with an investigational product or another systemic therapy administered in the last 3 weeks (except short acting SSA).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 177Lu-DOTA-Octreotate + talazoparib; Patients will receive 4 cycles of 177Lu-DOTA-Octreotate every 8 weeks, the last 3 cycles combined with talazoparib on days 2-6 of each cycle.	Drug: Talazoparib; During dose escalation, doses of talazoparib that can be administered are 0.1mg, 0.25mg, 0.5mg or 1mg oral daily. Talazoparib will be given on days 2-6 of each cycle of 177Lu-DOTA-Octreotate for cycles 2-4, every 8 weeks; Other Names: Combination product: 177Lu-DOTA-Octreotate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose Talazoparib with 177Lu-DOTA-Octreotate	Maximum tolerated dose of Talazoparib when given in combination with 177Lu-DOTA-Octreotate	Through study completion, up to 18 months following first administration of PRRT.
Dose limiting toxicity talazoparib	The toxicity (haematologic or non-haematologic) that prevents further administration of the trial talazoparib treatment at that dose level.	Each cohort of 3 patients be assessed for DLTs in the first 6 weeks (cycle 2) of treatment and a dose for the next cohort will be determined (each cycle is 8 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events and Serious Adverse Events measured using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0	Safety of the combination will be measured by AEs and SAEs	Through Study completion, up to 18 months after the last patient commences treatment.
Radiographic progression free survival	The time from treatment initiation to the first date of progression on imaging or death due to any cause. Imaging progression will be assessed by RECIST 1.1. Patients who commence new systemic therapy before evidence of disease progression on conventional imaging will be considered to have progressed.	Through study completion, up to 18 months following first administration of PRRT.
Overall Survival	The time from treatment initiation to the date of death due to any cause. For patients alive, the time will be censored at the last time the patients was known to be alive.	Through study completion, up to 18 months following first administration of PRRT.
Treatment discontinuation due to toxicity	The number of patients who discontinue treatment at any time due to treatment related toxicity will be reported and will be also categorised by dose level.	Through study completion, up to 18 months following first administration of PRRT.
Rate of Treatment discontinuation due to toxicity	The percentage of patients who discontinue treatment due to treatment related toxicity will be reported and will be also categorised by dose level	Through study completion, up to 18 months following first administration of PRRT.

Collaborators and Investigators

• Sponsor: Peter MacCallum Cancer Centre, Australia

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2021
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: September 2, 2021
• First Submitted That Met QC Criteria: September 20, 2021
• First Posted (Actual): September 23, 2021

Study Record Updates

• Last Update Posted (Actual): October 26, 2023
• Last Update Submitted That Met QC Criteria: October 24, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: NET
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Talazoparib
• Other Study ID Numbers: PMC67199

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No