Trial Title:
Propranolol and Pembrolizumab in Advanced Soft Tissue Sarcoma Patients
NCT ID:
NCT05961761
Condition:
Soft Tissue Sarcoma Adult
Angiosarcoma
Undifferentiated Pleomorphic Sarcoma
Conditions: Official terms:
Sarcoma
Hemangiosarcoma
Histiocytoma, Malignant Fibrous
Pembrolizumab
Propranolol
Conditions: Keywords:
Immunotherapy
Propranolol
Pembrolizumab
PD-1 inhibitor
Sarcoma
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
A Simon´s optimum two-stage design
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Propranolol
Description:
propranolol 40 mg x2 daily
Arm group label:
Propranolol + pembrolizumab
Other name:
Betablocker
Intervention type:
Drug
Intervention name:
Pembrolizumab
Description:
pembrolizumab 2 mg/kg every 3 weeks
Arm group label:
Propranolol + pembrolizumab
Other name:
anti PD-1
Summary:
The goal of this phase 2 clinical trial is to test efficacy and tolerability of combining
propranolol and pembrolizumab in patients with advanced angiosarcoma or undifferentiated
pleomorphic sarcoma. The main questions aims to answer:
- Primary: determine the progression-free survival rate (PFSR) at 3 months
Secondary: determine the objective response rate (ORR), duration of Response (DOR),
Progression Free Survival (PFS), Overall Survival (OS). Ensure the safety and
tolerability, Determine Quality of Life (QoL)
• Exploratory: Characterize the TME
Participants will be asked to ensure
- Baseline biopsy and further optional biopsies
- Treatment propranolol 40 mg BID and pembrolizumab 2 mg/kg Q3 weeks
- Evaluation, blood counts, QoL and blood samples for biomarkers according to schedule
Detailed description:
Soft tissue sarcomas (STS) are mesenchymal derived tumors consisting of more than 50
subtypes, showing high metastatic features in approximately 50% of patients with
intermediate and high-grade tumors. In spite of optimizing sequence of conventional
systemic treatments with chemotherapy and tyrosine kinase inhibitors with an increase in
overall survival from 12 to 18 months, the prognosis has not changed and is still a
dismal 8% overall survival at 5 years. After four decades doxorubicin is still first line
treatment as no new drugs has proven more effective and/or less toxic. Thus, new
treatment modalities are needed.
Angiosarcomas (AS) and Undifferentiated Pleomorphic Sarcoma (UPS), comprising
approximately 2% and 10% of STS respectively, are by definition high grade sarcomas
characterized by an aggressive course. In the non-resectable advanced and metastatic
setting treatment options are limited with short term palliative intent with median
overall survival (OS) < 12 months. Patients are often elderly and with co-morbidities,
increasing risk of severe toxicity from chemotherapy leading to significant deterioration
of Quality of Life. New therapeutic options are needed.
Emerging results on immune modulating therapy with immune checkpoint inhibitors (ICI),
have shown promising signals of potential benefit in certain subtypes of STS, especially
in UPS and AS.
In tumors, neovascularization facilitate hypoxia, glucose deprivation and increased VEGF
production leading to an immune suppressive tumor microenvironment (TME). This can in
part be reverted by anti-angiogenic therapy including multitarget tyrosine kinase
inhibitors. A proposed novel approach for targeting angiogenesis and potential immune
modulatory mechanisms is through beta-adrenergic receptor (βAR) signaling. Preclinical
data support combining βAR blockade with propranolol in combination with anti PD-1, and
recently a phase 1 study showed the combination propranolol and pembrolizumab was well
tolerated in melanoma patients.
This study is an open label, Simon two-stage single arm phase 2 study of pembrolizumab
and propranolol in two separate cohorts. Patients will receive pembrolizumab 2 mg/kg
every 3 weeks and propranolol 40 mg x2 daily until progression, unacceptable toxicity or
patient withdrawal for a maximum of two years.
Up to 40 patients will be included in each separate cohort. Up to 18 patients in stage 1
and up to 22 patients in stage 2.
The primary objective is to determine progression-free survival rate (PFSR) at 3 months
by Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
The secondary objectives are to determine objective response rate (ORR) and duration of
Response (DOR) using RECIST v 1.1, PFS and OS. Ensure safety and tolerability according
to Common Terminology Criteria for Adverse Events (CTCAE version 5.0), and determine
Quality of Life (QoL) using the 30 item European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30) questionnaire
The explorative objective is to characterize the TME, immune cells and markers both in
tumors and in peripheral blood.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Subjects must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be
obtained before the performance of any protocol related procedures that are not part
of normal subject care
- Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory testing, and other requirements of the study
- Histologically confirmed diagnosis of unresectable locally advanced or metastatic
Angiosarcoma or Undifferentiated Pleomorphic Sarcoma, who has progressed/failed to
provide clinical benefit on first line standard chemotherapy.
- Age ≥18 years
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤2 at the
time of enrollment.
- Evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST
version 1.1).
- Available material from archived formalin-fixed paraffin-embedded tumor tissue
obtained within 3 months of study enrollment for biomarker related studies. If not
sufficient or available, a newly obtained core or excisional biopsy of a tumor
lesion may be performed.
- Patients must have normal organ and marrow function as defined below:
- Absolute neutrophil count (ANC) ≥ 1 x 10⁹/L
- Platelet count ≥ 75 x 10⁹/L
- Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert's
Syndrome must have a total bilirubin ≤ 50 mmol/L)
- Aspartate transaminase (AST)/Alanine transaminase (ALT) ≤ 5 x ULN
- Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (using the
Cockcroft-Gault formula)
- Women of childbearing potential (WOCBP): Agreement to use contraceptive methods with
a failure rate of < 1 % per year during the treatment period and for at least 120
days after the treatment. Safe contraceptive methods for women are birth control
pills, intrauterine device, contraceptive injection, contraceptive
implant,contraceptive patch or contraceptive vaginal ring.
- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year during the treatment period and for at least
120 days after the treatment.
- Women who are not of childbearing potential (ie, who are postmenopausal or
surgically sterile) as well as azoospermic men do not require contraception
Exclusion Criteria:
- Have an anticipated life expectancy of <3 months.
- Moderate to severe degree of bronchial asthma or chronic obstructive pulmonary
disease.
- Acute or non-stable congestive heart failure
- Any other condition listed as contraindication for treatment with propranolol
according to SPC
- Have received any previous systemic therapy targeting the PD-1/PDL-1 signaling
pathway or other immune checkpoint inhibitors.
- Have received propranolol within 4 weeks prior to treatment.
- Prior to study day one received radiation therapy, chemotherapy or targeted small
molecule therapy within 2 weeks and/or monoclonal antibody treatment within 4 weeks.
- Not recovered from the effects of previously administered agents
- Clinically active or unstable CNS metastases as assessed by the treating physician
- Any serious or uncontrolled medical disorder that, in the opinion of the
investigator, may increase the risk associated with study participation or study
drug administration, impair the ability of the subject to receive protocol therapy,
or interfere with the interpretation of study results
- Participants with active, known or suspected autoimmune disease. Participants with
vitiligo, type I diabetes mellitus, residual hypothyroidism Inclusion criteria
- Subjects must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be
obtained before the performance of any protocol related procedures that are not part
of normal subject care
- Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory testing, and other requirements of the study
- Histologically confirmed diagnosis of unresectable locally advanced or metastatic
Angiosarcoma or Undifferentiated Pleomorphic Sarcoma, who has progressed/failed to
provide clinical benefit on first line standard chemotherapy.
- Age ≥18 years
- Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤2 at the
time of enrollment.
- Evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST
version 1.1).
- Available material from archived formalin-fixed paraffin-embedded tumor tissue
obtained within 3 months of study enrollment for biomarker related studies. If not
sufficient or available, a newly obtained core or excisional biopsy of a tumor
lesion may be performed.
- Patients must have normal organ and marrow function as defined below:
- Absolute neutrophil count (ANC) ≥ 1 x 10⁹/L
- Platelet count ≥ 75 x 10⁹/L
- Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert's
Syndrome must have a total bilirubin ≤ 50 mmol/L)
- Aspartate transaminase (AST)/Alanine transaminase (ALT) ≤ 5 x ULN
- Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (using the
Cockcroft-Gault formula)
- Women of childbearing potential (WOCBP): Agreement to use contraceptive methods with
a failure rate of < 1 % per year during the treatment period and for at least 120
days after the treatment. Safe contraceptive methods for women are birth control
pills, intrauterine device, contraceptive injection, contraceptive
implant,contraceptive patch or contraceptive vaginal ring.
- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year during the treatment period and for at least
120 days after the treatment.
- Women who are not of childbearing potential (ie, who are postmenopausal or
surgically sterile) as well as azoospermic men do not require contraception
Exclusion criteria
- Have an anticipated life expectancy of <3 months.
- Moderate to severe degree of bronchial asthma or chronic obstructive pulmonary
disease.
- Acute or non-stable congestive heart failure
- Any other condition listed as contraindication for treatment with propranolol
according to SPC
- Have received any previous systemic therapy targeting the PD-1/PDL-1 signaling
pathway or other immune checkpoint inhibitors.
- Have received propranolol within 4 weeks prior to treatment.
- Prior to study day one received radiation therapy, chemotherapy or targeted small
molecule therapy within 2 weeks and/or monoclonal antibody treatment within 4 weeks.
- Not recovered from the effects of previously administered agents
- Clinically active or unstable CNS metastases as assessed by the treating physician
- Any serious or uncontrolled medical disorder that, in the opinion of the
investigator, may increase the risk associated with study participation or study
drug administration, impair the ability of the subject to receive protocol therapy,
or interfere with the interpretation of study results
- Participants with active, known or suspected autoimmune disease. Participants with
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are permitted to enroll.
- Participants with a condition requiring systemic treatment with either
corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive
medications. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune disease.
- Patients should be excluded if they have known history of testing positive for human
immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- Allergies and Adverse Drug Reaction
- History of allergy to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
- WOCBP who are pregnant or breastfeeding
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Aarhus University Hospital
Address:
City:
Aarhus
Zip:
8200
Country:
Denmark
Status:
Not yet recruiting
Contact:
Last name:
Ninna Aggerholm Pedersen, MD, PhD, Msc
Email:
aggerholm@oncology.au.dk
Facility:
Name:
Herlev Gentofte Hospital
Address:
City:
Herlev
Zip:
2730
Country:
Denmark
Status:
Recruiting
Contact:
Last name:
Niels Junker, MD, PhD
Phone:
+4538682973
Email:
Niels.Junker@regionh.dk
Facility:
Name:
Oslo University Hospital
Address:
City:
Oslo
Country:
Norway
Status:
Recruiting
Contact:
Last name:
Kjetil Boye, MD, PhD
Email:
kjetil.boye@ous-hf.no
Facility:
Name:
Karolinska University Hospital
Address:
City:
Stockholm
Country:
Sweden
Status:
Not yet recruiting
Contact:
Last name:
Andri Papakonstantinou, MD, PhD
Email:
andri.papakonstantinou@regionstockholm.se
Start date:
August 17, 2021
Completion date:
December 2028
Lead sponsor:
Agency:
Niels Junker
Agency class:
Other
Collaborator:
Agency:
Aarhus University Hospital
Agency class:
Other
Collaborator:
Agency:
Oslo University Hospital
Agency class:
Other
Collaborator:
Agency:
Karolinska University Hospital
Agency class:
Other
Source:
Herlev and Gentofte Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05961761
