Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial) (SALE)
Primary Purpose
Pancreatic Ductal Adenocarcinoma
Status
Active
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Chlorambucil, Oral, 2 Mg
Sponsored by

About this trial
This is an interventional treatment trial for Pancreatic Ductal Adenocarcinoma focused on measuring chlorambucil, BRCA mutations, DNA defect repair mutations
Eligibility Criteria
Inclusion Criteria:
- 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
- More than 2 weeks since prior chemotherapy end
- Signed written informed consent
- QTc <450 msec or QTc <480 msec for patients with bundle branch block
Exclusion Criteria:
- 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
- Any condition that confounds the ability to interpret data from the study
- Any familiar, sociologic or geographic conditions that can potentially interfere with the adhesion to the protocol or to the follow-up
- 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).
- Concurrent treatment with other experimental drugs
Sites / Locations
- IRCCS San Raffaele
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Chlorambucil
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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
Radiological response rate
Radiological response evaluation by using RECIST 1.1 criteria
Biochemical response rate
Biochemical response evaluation by testing Ca19.9 marker
Drug safety
Drug toxicity evaluation by using appropriate SAE report form
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04692740
Brief Title
Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial)
Acronym
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.
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 18, 2020 (Actual)
Primary Completion Date
January 4, 2023 (Actual)
Study Completion Date
December 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Michele Reni
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
Detailed 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pancreatic Ductal Adenocarcinoma
Keywords
chlorambucil, BRCA mutations, DNA defect repair mutations
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Chlorambucil
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Chlorambucil, Oral, 2 Mg
Intervention Description
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.
Primary Outcome Measure Information:
Title
Progression free survival evaluation
Description
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.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Overall survival evaluation
Description
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
Time Frame
36 months
Title
Radiological response rate
Description
Radiological response evaluation by using RECIST 1.1 criteria
Time Frame
6 months
Title
Biochemical response rate
Description
Biochemical response evaluation by testing Ca19.9 marker
Time Frame
6 months
Title
Drug safety
Description
Drug toxicity evaluation by using appropriate SAE report form
Time Frame
6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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
More than 2 weeks since prior chemotherapy end
Signed written informed consent
QTc <450 msec or QTc <480 msec for patients with bundle branch block
Exclusion Criteria:
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
Any condition that confounds the ability to interpret data from the study
Any familiar, sociologic or geographic conditions that can potentially interfere with the adhesion to the protocol or to the follow-up
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).
Concurrent treatment with other experimental drugs
Facility Information:
Facility Name
IRCCS San Raffaele
City
Milan
ZIP/Postal Code
20132
Country
Italy
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
26909576
Citation
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.
Results Reference
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PubMed Identifier
29069866
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.
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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.
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Chlorambucil in Metastatic PDAC Patients Bearing a Germ Line DNA Defects Repair Mutations (SALE Trial)
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