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

Pancreatic Ductal Adenocarcinoma Clinical Trial

— SALE  

Official title:

A Pilot Study of Chlorambucil in Pre-treated Metastatic Pancreatic Adenocarcinoma Patients Bearing a Germ Line BRCA or Other DNA Defects Repair (DDR) Mutations.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04692740
• Other study ID #: PACT29
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 18, 2020
• Est. completion date: December 2023

Study information

• Verified date: September 2023
• Source: IRCCS San Raffaele
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Nowadays, treatment strategies for patients affected by metastatic pancreatic ductal adenocarcinoma (PDAC) are still very scant. Gemcitabine and fluoropyrimidine based chemotherapy regimens are standard I line chemotherapy. Recently, landmark genome-wide studies revealed the existence of a distinct subpopulation of PDAC with highly unstable genomic properties, due to mutations in DNA Damage Repair genes (DDR), in particular BRCA1/2 mutations. Germline mutations cause a deficiency in deoxyribonucleic acid (DNA) damage repair due to inhibition of DNA double-strand breaks repair by the mechanism of homologous recombination. Cancer cells rely on DNA repair to survive the damage induced by genotoxic stress and DNA repair enables cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype. BRCA1/2 abrogation and homologous repair deficiency (HRD) confer sensitivity to DNA damage-inducing drugs, in particular those inflicting cytotoxic DNA crosslinks that interfere with DNA replication. The sensitivity of BRCA1/2-mutated tumors to platinum compounds has been validated in multiple pre-clinical and clinical studies. Nevertheless, similar lesions are induced by DNA-alkylating agents, which include mono-functional (e.g. mitomycin C) or bifunctional alkylators (e.g. chlorambucil). Small molecule inhibitors of poly(ADP-ribose) polymerase (PARP) have been recently developed and they showed an interesting activity and efficacy in breast, ovarian and pancreatic cancer tumors. Although platinum drugs and PARP inhibitors show initially good responses in the clinic, most patients acquire resistance to these drugs. Chlorambucil shows high selective toxicity against human cells and xenograft tumors with compromised BRCA1/2 function. Patients affected by metastatic ductal adenocarcinoma, pretreated with at least one previous platinum-based chemotherapy, will be treated with oral chlorambucil for 42 consecutive days After restaging, responder patients and those with stable disease will receive for 14 consecutive days every 28 days until disease progression (RECIST 1.1 criteria) or unbearable toxicity, patient refusal or medical decision.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: December 2023
• Est. primary completion date: January 4, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Pathologically confirmed pancreatic adenocarcinoma

2. Age = 18 years

3. ECOG PS 0-2

4. Stage IV disease

5. Identified genetic aberrations that are associated with homologous recombination deficiency (HRD)

1. Cohort A: Documented mutation in gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious

2. Cohort B: BRCA1 or BRCA2 mutations that are considered to be of uncertain/unknown significance (VUS)

3. Cohort C: Patients with other identified genetic aberrations that are associated with HRD

6. Adequate PFS during previous platinum-based chemotherapy for at least 4 months before progression

7. 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.

8. Able to take oral medication

9. Progression during or after platinum-based chemotherapy

10. Other prior chemotherapy apart from first-line treatment for pancreatic cancer, are allowed, including maintenance treatment with PARP inhibitors

11. More than 2 weeks since prior chemotherapy end

12. Signed written informed consent

13. QTc <450 msec or QTc <480 msec for patients with bundle branch block

Exclusion Criteria:

1. 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

2. Active and uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy

3. Vaccination with vaccines called "live", since this treatment causes a drop of immunity defenses and a serious infection could result fatal.

4. History of seizure, head trauma and treatment with anti-epileptogenic drugs

5. Hypersensitivity to chlorambucil or to any excipients, in particular lactose

6. Recent radiotherapy (at least 4 weeks) or previous treatment with other cytotoxic agents

7. BRCA-mutated advanced pancreatic cancer who did not undergo maintenance with olaparib after platinum-based chemotherapy

8. 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

9. Concomitant PARP inhibitors therapy

10. Life expectancy less than 3 months, in the opinion of the investigator

11. 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

12. Symptomatic duodenal stenosis

13. CT contrast medium allergy and claustrophobia to RM investigation

14. Any significant medical condition laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study

15. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study

16. Any condition that confounds the ability to interpret data from the study

17. Any familiar, sociologic or geographic conditions that can potentially interfere with the adhesion to the protocol or to the follow-up

18. Pregnant or nursing. Adequate contraception is defined as oral hormonal birth control, intrauterine device, and male partner sterilization (if male partner is sole partner for that subject) and the double barrier method (condom or occlusive cap plus spermicidal agent).

19. Concurrent treatment with other experimental drugs

Related Conditions & MeSH terms

• Adenocarcinoma
• Pancreatic Ductal Adenocarcinoma

Intervention

Drug:
• Chlorambucil, Oral, 2 Mg
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.

Locations

Country	Name	City	State
Italy	IRCCS San Raffaele	Milan

Sponsors (1)

Lead Sponsor	Collaborator
Michele Reni

Country where clinical trial is conducted

Italy, 

References & 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Overall survival evaluation	Overall survival (OS) is defined as time between the date of registration and the date of death for any cause or the date they were last known to be alive	36 months
Secondary	Radiological response rate	Radiological response evaluation by using RECIST 1.1 criteria	6 months
Secondary	Biochemical response rate	Biochemical response evaluation by testing Ca19.9 marker	6 months
Secondary	Drug safety	Drug toxicity evaluation by using appropriate SAE report form	6 months