Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial)

NCT04692740 | Unknown Phase 2

• 1 other identifier: PACT29
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The main objective of this trial is to explore the activity of chlorambucil, an alkylating agent commonly used in chronic lymphocytic leukemia treatment, in metastatic patients, gBRCA, including VUS, or DDR mutated, previously treated with a platinum-containing chemotherapy.

Conditions

Pancreatic Ductal Adenocarcinoma

Keywords

chlorambucil; BRCA mutations; DNA defect repair mutations

Outcome Measures

Primary Outcomes (1)

• Progression free survival evaluation

  Evaluate the proportion of patients who are progression-free defined as progression according to RECIST 1.1 criteria or death. Progression free survival (PFS) is defined as the time between the date of registration and the date of documented radiological PD according to RECIST 1.1 criteria or death from any cause, whichever occurs first, or the date of last follow-up or last available tumour assessment if no further follow-up for disease progression is performed.

  6 months

Secondary Outcomes (4)

• Overall survival evaluation

  36 months

• Radiological response rate

  6 months

• Biochemical response rate

  6 months

• Drug safety

  6 months

Study Arms (1)

Chlorambucil

EXPERIMENTAL

Drug: Chlorambucil, Oral, 2 Mg

Interventions

Chlorambucil, Oral, 2 Mg DRUG

Eligible patients will be treated with Chlorambucil 6 mg/m2 daily p.o. for 42 consecutive days (weeks 1-6). After restaging, responder patients (complete or partial response) and those with stable disease will receive Chlorambucil 6 mg/m2 daily p.o for 14 consecutive days every 28 days until disease progression or unbearable toxicity, patient refusal or medical decision. Patients' clinical data will be collected pseudo-anonymously and a sequential identification code number will be assigned to each patient enrolled in the study.

Chlorambucil

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pathologically confirmed pancreatic adenocarcinoma
• Age ≥ 18 years
• ECOG PS 0-2
• Stage IV disease
• Identified genetic aberrations that are associated with homologous recombination deficiency (HRD)
• Cohort A: Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious
• Cohort B: BRCA1 or BRCA2 mutations that are considered to be of uncertain/unknown significance (VUS)
• Cohort C: Patients with other identified genetic aberrations that are associated with HRD
• Adequate PFS during previous platinum-based chemotherapy for at least 4 months before progression
• Screening laboratory values:
• Leukocytes \> 3000/mmc Thrombocytes \> 150000/mmc Hemoglobin \> 10 g/dl Creatinine \<2.0 times upper normal limit (unless normal creatinine clearance). Total bilirubin \< 2.0 times upper normal limit (unless due to Gilbert's syndrome).
• Alanine aminotransferase (ALT) \< 3.0 times upper normal limit.
• Able to take oral medication
• Progression during or after platinum-based chemotherapy
• Other prior chemotherapy apart from first-line treatment for pancreatic cancer, are allowed, including maintenance treatment with PARP inhibitors

You may not qualify if:

• Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to screening, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities
• Active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy
• Vaccination with vaccines called "live", since this treatment causes a drop of immunity defenses and a serious infection could result fatal.
• History of seizure, head trauma and treatment with anti-epileptogenic drugs
• Hypersensitivity to chlorambucil or to any excipients, in particular lactose
• Recent radiotherapy (at least 4 weeks) or previous treatment with other cytotoxic agents
• BRCA-mutated advanced pancreatic cancer who did not undergo maintenance with olaparib after platinum-based chemotherapy
• Mismatch repair (MMR)/high levels of microsatellite instability (MSI-H), or high levels of tumor mutational burden (TMB) pancreatic cancer who did not undergo immunotherapy with pembrolizumab monotherapy or any other anti-PD1 agent
• Concomitant PARP inhibitors therapy
• Life expectancy less than 3 months, in the opinion of the investigator
• Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible
• Symptomatic duodenal stenosis
• CT contrast medium allergy and claustrophobia to RM investigation
• Any significant medical condition laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
• Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study

Sponsors & Collaborators

• Michele Reni: lead

Study Sites (1)

IRCCS San Raffaele

Milan, 20132, Italy

Location

Related Publications (5)

• Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grutzmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM; Australian Pancreatic Cancer Genome Initiative; Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, Grimmond SM. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24.

  PMID: 26909576 BACKGROUND

• Pihlak R, Valle JW, McNamara MG. Germline mutations in pancreatic cancer and potential new therapeutic options. Oncotarget. 2017 Apr 20;8(42):73240-73257. doi: 10.18632/oncotarget.17291. eCollection 2017 Sep 22.

  PMID: 29069866 BACKGROUND

• Rebelatto TF, Falavigna M, Pozzari M, Spada F, Cella CA, Laffi A, Pellicori S, Fazio N. Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis. Cancer Treat Rev. 2019 Nov;80:101895. doi: 10.1016/j.ctrv.2019.101895. Epub 2019 Sep 6.

  PMID: 31542591 BACKGROUND

• Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, Park JO, Hochhauser D, Arnold D, Oh DY, Reinacher-Schick A, Tortora G, Algul H, O'Reilly EM, McGuinness D, Cui KY, Schlienger K, Locker GY, Kindler HL. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. doi: 10.1056/NEJMoa1903387. Epub 2019 Jun 2.

  PMID: 31157963 BACKGROUND

• Tacconi EM, Badie S, De Gregoriis G, Reislander T, Lai X, Porru M, Folio C, Moore J, Kopp A, Baguna Torres J, Sneddon D, Green M, Dedic S, Lee JW, Batra AS, Rueda OM, Bruna A, Leonetti C, Caldas C, Cornelissen B, Brino L, Ryan A, Biroccio A, Tarsounas M. Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance. EMBO Mol Med. 2019 Jul;11(7):e9982. doi: 10.15252/emmm.201809982. Epub 2019 May 24.

  PMID: 31273933 BACKGROUND

MeSH Terms

Interventions

Chlorambucil

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: December 30, 2020
• First Posted: January 5, 2021
• Study Start: December 18, 2020
• Primary Completion: January 4, 2023
• Study Completion: December 1, 2023
• Last Updated: September 21, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)