Trial Title:
Study Evaluating Pembrolizumab +/- Olaparib in TLS Positive Selected Resectable STS Followed by Adjuvant Pembrolizumab
NCT ID:
NCT06116578
Condition:
Cancer
Conditions: Official terms:
Pembrolizumab
Olaparib
Conditions: Keywords:
sarcoma
TLS
Liposarcoma
immunotherapy
PARP
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Pembrolizumab
Description:
cf Arm A
Arm group label:
A: Pembrolizumab before surgery
Other name:
WOO (Windows of opportunity)
Intervention type:
Drug
Intervention name:
Pembrolizumab and Olaparib
Description:
cf Arm B
Arm group label:
B: Pembrolizumab + olaparib before surgery
Other name:
WOO (Windows of opportunity)
Intervention type:
Drug
Intervention name:
Pembrolizumab adjuvant
Description:
After surgery (adjuvant phase), all patients (Arm A and B) will receive pembrolizumab 200
mg two intravenous (IV) infusions q3w for one-year
Arm group label:
A: Pembrolizumab before surgery
Arm group label:
B: Pembrolizumab + olaparib before surgery
Other name:
Adjuvant
Summary:
Soft tissue sarcomas represent a subtype of cancer that is both rare and very
heterogeneous. When they are organized, their current treatment is essentially based on
tumor resection surgery, +/- associated with treatment by chemotherapy and/or
radiotherapy. The aim of this treatment is to reduce the risk of local recurrence
(appearance of a tumor in the same region where it was first detected) and/or distant
(appearance of a tumor in other regions, organs where it was first detected).
Currently, no immunotherapy treatment has been approved for the treatment of patients
with sarcoma.
This research is based on the hypothesis that soft tissue sarcomas in which "tertiary
lymphoid structures" or "TLS" are found, recognizable by a cluster of specific immune
cells within the tumor, would be likely to respond better to the immunotherapy.
Furthermore, the combination of immunotherapy and certain drugs targeting DNA repair has
demonstrated some effectiveness in other types of cancers.
The research will therefore focus on two experimental drugs :
- Pembrolizumab (immunotherapy) and
- Olaparib (DNA repair inhibitor).
This research will make it possible to evaluate the effectiveness and safety of use of
the two drugs.
Detailed description:
This study will allow:
- To evaluate the ability of pembrolizumab (with or without olaparib) before surgery
to trigger an immune reaction in order to kill tumor cells.
- To evaluate the feasibility of therapy with pembrolizumab for 1 year (with or
without radiotherapy) after surgery.
The research is divided into two groups of patients, called "cohorts" depending on the
type of soft tissue sarcoma you have:
- Cohort 1: Undifferentiated pleomorphic sarcoma
- Cohort 2: Dedifferentiated liposarcoma
Before surgery, a group of patients will receive pembrolizumab combined with olaparib, a
second group will receive only pembrolizumab. All patients will receive pembrolizumab
after surgery (for up to 1 year).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Male or female patients aged ≥ 18 years at time of informed consent signature
- Histologically confirmed diagnosis of high grade (FNCLCC grade 2 or 3) extremity,
retroperitoneal, or trunk wall STS of selected histotypes as defined below.
Diagnosis must be stated in a pathology report and confirmed by the physician
investigator:
Cohort 1: Undifferentiated Pleomorphic Sarcoma (UPS) Cohort 2: Dedifferentiated
Liposarcoma (ddLPS)
- R0 resectability at time of enrollment according to expert STS surgeon
- Absence of distant metastasis on screening CT-scan (or equivalent appropriate
imaging technique)
- Patients with local relapse after an initial surgical resection can be enrolled if
no perioperative chemotherapy or radiation has been previously performed
Identification of Tertiary Lymphoid Structures (TLSs) on tumor archival FFPE sample,
as assessed by a registered STS expert senior pathologist
- Primary tumor site measurable according to RECIST v1.1 as ≥10 mm in the longest
diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed
tomography (CT) or magnetic resonance imaging (MRI) and suitable for repeated
assessment.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no
deterioration from registration date
- Adequate hematologic and organ function, defined by the following laboratory results
obtained within 3 days prior to the first study treatment (Cycle 0 Day 1): Absolute
neutrophil count (ANC) ≥ 1500 cells/μL, Platelet count ≥ 100.000/μL, Hemoglobin ≥ 10
g/dL, Total bilirubin ≤ 1.5 ULN (subjects with documented/suspected Gilbert's
disease may be enrolled with bilirubin ≤ 3 × ULN), Aspartate aminotransferase (AST)
and Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit (ULN), Albumin ≥
28g/L, Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 30 mL/min (according
to Cockcroft and Gault formula), International normalized ratio (INR) and activated
partial thromboplastin time (aPTT) ≤ 1.5 x ULN. This applies only to patients who do
not receive therapeutic anticoagulation; patients receiving therapeutic
anticoagulation (such as low-molecular weight heparin or warfarin) should be on
stable dose.
- Hepatitis B and C, and HIV screening tests are not required unless
- Known history of HBV, HCV or HIV infection
- As mandated by local health authority
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) OR
2. A WOCBP who agrees to follow the contraceptive guidance during the treatment
period and for 120 to 180 days (corresponding to time needed to eliminate any
study treatment(s) plus the duration of a menstruation cycle: 120 days for
pembrolizumab and/or 180 days for olaparib) after the last dose of study
treatment.
Male participants:
A male participant must agree to use a contraception - Contraceptive Guidance and
Pregnancy Testing of this protocol during the treatment period and for at least 180 to
240 days, corresponding to time needed to eliminate any study treatment(s) plus the
duration of a spermatogenesis cycle: 180 for pembrolizumab and/or 240 days for olaparib)
after the last dose of study treatment and refrain from donating sperm during this
period.
- Participant must agree to not donate blood during the study or for 90 days after the
last dose of study treatment.
- Patient should understand, sign, and date the written informed consent form prior to
any protocol-specific procedures performed.
- Patient should be able and willing to comply with baseline mandatory biopsy, as well
as study visits and procedures as per protocol.
- Patients must be affiliated to a social security system or beneficiary of an
equivalent system.
Exclusion Criteria:
- Has a visceral STS primary site.
- Has a non-resectable or marginally resectable locally advanced STS, as assessed by
expert STS surgeon.
- Has evidence of metastatic disease on CT-scan (or equivalent imaging technique).
- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to randomization.
- Has received prior radiotherapy within 2 weeks of start of study intervention or
radiation-related toxicities requiring corticosteroids.
- Has had previous exposure to anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an
agent directed to another stimulatory or co inhibitory T-cell receptor (e.g.,
CTLA-4, OX 40, CD137).
- Had had previous exposure to olaparib or any other PARP inhibitor.
- Has received a live vaccine or live-attenuated vaccine received within 4 weeks prior
to Cycle 0 Day 1 or anticipation that such a live attenuated vaccine will be
required during the study. Administration of killed vaccines is allowed.
- Has received treatment with systemic immunostimulatory agents (e.g., IFN and IL-2)
within 4 weeks prior to Cycle 0 Day 1.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
- Has had an administration of colony stimulating factors (e.g., granulocyte
colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
recombinant erythropoietin) within 4 weeks prior to Cycle 0 Day 1.
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to
randomization (see Appendix 3 - Contraceptive Guidance and Pregnancy Testing). If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.
- Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
- Has a history of severe allergic, anaphylactic, or other hypersensitivity reactions
to the components of excipients in pembrolizumab and/or olaparib.
- Has any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia
(AML) or immunodeficiency
- Has active autoimmune disease that has required systemic treatment in the past 2
years except replacement therapy (e.g.., thyroxine, insulin, or physiologic
corticosteroid)
- Has a history of (non-infectious) pneumonitis/interstitial lung disease that
required steroids or has current pneumonitis/interstitial lung disease.
- Has a history of allogeneic tissue/organ or hematopoietic stem cell transplantation.
- Has a history of another primary malignancy within 2 years prior to Cycle 0 Day 1
- Has a serious, uncontrolled medical disorder
- Is unable to swallow orally administered medication or has a gastrointestinal
disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, and
malabsorption).
- Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV
DNA), Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA)
infection, HIV (defined as detectable viral load)
- Has any active infection requiring systemic therapy.
- Major surgical procedure within 20 days prior ty Cycle 0 Day 1 or anticipation of
need for a major surgical procedure during the course of the study.
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality or other circumstance that might confound the results of the study,
interfere with the participant's participation for the full duration of the study,
such that it is not in the best interest of the participant to participate, in the
opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Participant is currently receiving either strong (e.g., itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin,
erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450
(CYP)3A4 that cannot be discontinued for the duration of the study. The required
washout period prior to starting olaparib is 2 weeks. The medication can be
restarted as soon as olaparib has been halted.
- Participant is currently receiving either strong (phenobarbital, enzalutamide,
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St
John's Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4
that cannot be discontinued for the duration of the study. The required washout
period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other
agents. The medication can be restarted as soon as olaparib has been halted.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Gustave Roussy
Address:
City:
Villejuif
Zip:
94800
Country:
France
Start date:
September 2024
Completion date:
June 2028
Lead sponsor:
Agency:
Gustave Roussy, Cancer Campus, Grand Paris
Agency class:
Other
Collaborator:
Agency:
Merck Sharp & Dohme LLC
Agency class:
Industry
Source:
Gustave Roussy, Cancer Campus, Grand Paris
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06116578
