Pembrolizumab in Treating Patients With Rare Tumors That Cannot Be Removed by Surgery or Are Metastatic

Advanced Malignant Solid Neoplasm Clinical Trial

Official title:

Phase II Study for the Evaluation of Efficacy of Pembrolizumab (MK-3475) in Patients With Rare Tumors

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02721732
• Other study ID #: 2015-0948
• Secondary ID: NCI-2016-0054520
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 15, 2016
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: M.D. Anderson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well pembrolizumab works in treating patients with rare tumors that cannot be removed by surgery or have spread to other parts of the body. Monoclonal antibodies, such as pembrolizumab, may block specific proteins found on white blood cells which may strengthen the immune system and control tumor growth.

Description:

PRIMARY OBJECTIVES:

I. To obtain early indication of efficacy by evaluation of non-progression rate (NPR) at 27 weeks as defined as the percentage of patients who are alive and progression-free at 27 weeks as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 or immune-related(ir)RECIST or method of tumor evaluation criteria best suitable and accepted for the tumor type evaluated in patients with advanced tumor types receiving pembrolizumab.

SECONDARY OBJECTIVES:

I. To correlate efficacy by evaluation of tumor size to programmed cell death 1 ligand 1 (PD-L1) status among patients with advanced tumor types receiving pembrolizumab.

II. To evaluate safety and tolerability of pembrolizumab in patients with advanced tumors.

III. To evaluate the percentage of patients with objective response (complete response [CR] or partial response [PR]), clinical benefit (CR, PR, or stable disease [SD] >= 4 months), progression free survival (PFS), overall survival (OS), and duration of response (DOR) as assessed by RECIST v1.1 in patients with advanced tumor types receiving pembrolizumab.

IV. To evaluate the percentage of patients with objective response (CR or PR), clinical benefit (CR, PR, or SD >= 4 months), PFS, and DOR as assessed by irRECIST in patients with advanced tumor types receiving pembrolizumab.

V. To correlate the NPR at 27 weeks (9 cycles), objective response (CR or PR), clinical benefit CR, PR, or SD >= 4 months), PFS, OS, and DOR to PD-L1 status among patients with advanced tumor types receiving pembrolizumab.

EXPLORATORY OBJECTIVES:

I. To evaluate the potential role of tumor-associated immune biomarkers for prediction of therapy effectiveness in patients with advanced tumor types receiving pembrolizumab.

II. To correlate the potential role of tumor-associated immune biomarkers for prediction of therapy effectiveness to PD-L1 status among patients with advanced tumor types receiving pembrolizumab.

III. To identify imaging characteristics associated with immunological changes in tumor following treatment with pembrolizumab.

IV. To compare tumor mutation burden and serial assessment of mutation status in biopsies obtained at baseline and progression in patients with advanced tumor types receiving pembrolizumab.

V. To evaluate patient-reported outcomes (PRO) utilizing the National Cancer Institute (NCI) Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaires.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or toxicity. Patients with clinical response or disease stabilization may continue treatment for up to an additional 12 months.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 157
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Be willing and able to provide written informed consent/assent for the trial

• Have measurable disease based on RECIST 1.1 or irRECIST; only cohort 9 and 10 can have evaluable disease (non-measurable lesions); tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions; patients may have bone metastatic disease evaluable according to tumor evaluation criteria best suitable and accepted for the tumor type evaluated

• Have one of the following advanced (unresectable and/or metastatic) solid tumor indications that has progressed following standard therapies, where standard therapies are available:

• Squamous cell carcinoma of the skin

• Small cell malignancies of non-pulmonary origin

• Adrenocortical carcinoma

• Medullary renal cell carcinoma

• Carcinoma of unknown primary

• Penile carcinoma

• Vascular sarcoma

• Germ cell tumor

• Paraganglioma-pheochromocytoma

• Other rare tumors (except those tumor types listed in exclusion)

• Have failed prior treatment within 6 months of consent date

• Have biopsiable disease; subjects must have at least one lesion amenable to biopsy; tumor lesions used for biopsy should not be lesions used as target lesions; in cohort 9: paraganglioma-pheochromocytoma or cohort 10, where there is prominent bony disease, biopsies may not be possible due to the nature of the disease

• Be willing to provide archival tissue; if archival tissue is not available, or a newly obtained core or excisional biopsy of a tumor lesion will be obtained; newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; in cohort 9: paraganglioma-pheochromocytoma or cohort 10, where there is prominent bony disease, biopsies may not be possible due to the nature of the disease

• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale

• Absolute neutrophil count (ANC) >= 1,000/mcL (performed within 28 days of treatment initiation)

• Platelets >= 75,000/mcL (performed within 28 days of treatment initiation)

• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 28 days of treatment initiation)

• Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 28 days of treatment initiation)

• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 28 days of treatment initiation)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 28 days of treatment initiation)

• Albumin > 2.5 mg/dL (performed within 28 days of treatment initiation)

• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 28 days of treatment initiation)

• Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 28 days of treatment initiation)

• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year

• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

• For subjects in cohort 2 (small cell malignancies of non-pulmonary origin), confirmation of no brain metastases via imaging

Exclusion Criteria:

• Is currently participating and receiving study therapy or concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment at the time of administration of first dose of trial treatment; continuation of hormone replacement therapy is permitted; stable regimens of hormonal therapy i.e. for prostate cancer (e.g. leuprolide, a gonadotrophin releasing hormone [GnRH] agonist), ovarian, or breast cancer are not exclusionary

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment

• Has a known history of active TB (bacillus tuberculosis)

• Hypersensitivity to pembrolizumab or any of its excipients

• Has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent; Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study; Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, and diseases for which the treatment could reasonably include pembrolizumab and are not part of the excluded tumor type list or not eligible for the phase I trial

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; immunosuppressive corticosteroid doses (> 10 mg prednisone daily or equivalent) within 4 weeks prior to the first dose of pembrolizumab; Note: corticosteroids given within 24 hours of an imaging study for purposes of pre-medication in patients with hypersensitivity to radiologic contrast agents are allowed

• Has known history of, or any evidence of active, non-infectious pneumonitis

• Has an active infection requiring systemic therapy

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject 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

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

• Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

• Has received a live vaccine within 30 days of planned start of study therapy; Note:

seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed

• Is participating in cohort 10 and has melanoma; non-small cell lung cancer; hepatocellular carcinoma; Merkel cell carcinoma; colon or rectal adenocarcinoma; anal canal squamous cell carcinoma; pancreas adenocarcinoma; esophageal squamous cell carcinoma or adenocarcinoma (including gastroesophageal [GE] junction); biliary tract adenocarcinoma (gallbladder and biliary tree but excluding ampulla of vater cancers); carcinoid tumors; neuroendocrine carcinomas (well or moderately differentiated pancreatic neuroendocrine tumor); estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer; triple negative breast cancer; ovarian epithelial, fallopian tube or primary peritoneal carcinoma; endometrial carcinoma; cervical squamous cell cancer; vulvar squamous cell carcinoma; small cell lung cancer; mesothelioma (malignant pleural mesothelioma); thyroid cancer (papillary or follicular subtype); salivary gland carcinoma; nasopharyngeal carcinoma; glioblastoma multiforme; leiomyosarcoma; prostate adenocarcinoma; gastric adenocarcinoma; or small bowel malignancy

Related Conditions & MeSH terms

• Adrenocortical Carcinoma
• Advanced Malignant Solid Neoplasm
• Carcinoma
• Carcinoma of Unknown Primary
• Carcinoma, Renal Cell
• Carcinoma, Small Cell
• Carcinoma, Squamous Cell
• Metastatic Adrenal Gland Pheochromocytoma
• Metastatic Kidney Medullary Carcinoma
• Metastatic Malignant Germ Cell Tumor
• Metastatic Malignant Solid Neoplasm
• Metastatic Paraganglioma
• Metastatic Penile Carcinoma
• Metastatic Skin Squamous Cell Carcinoma
• Neoplasms
• Paraganglioma
• Penile Neoplasms
• Pheochromocytoma
• Small Cell Carcinoma
• Small Cell Lung Carcinoma
• Stage III Adrenal Cortex Carcinoma AJCC v7
• Stage IV Adrenal Cortex Carcinoma AJCC v7
• Stage IV Penile Cancer AJCC v7
• Stage IV Renal Cell Cancer AJCC v7
• Unresectable Adrenal Gland Pheochromocytoma
• Unresectable Paraganglioma
• Unresectable Skin Squamous Cell Carcinoma
• Unresectable Solid Neoplasm
• Vascular Neoplasm

Intervention

Other:
• Laboratory Biomarker Analysis
Correlative studies

Biological:
• Pembrolizumab
Given IV

Other:
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
United States	M D Anderson Cancer Center	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Non-progression Rate (NPR) at 27 Weeks by irRECIST	Non-progression rate (NPR) at 27 weeks was defined as the percentage of efficacy evaluable patients who were alive and progression-free at 27 weeks as assessed by irRECIST; Progression is defined using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST), as an increase = 20% (minimum 5 mm) in total measured tumor burden compared with nadir or progression of non-target lesions or new lesion	At 27 weeks
Secondary	Evaluation of Tumor Size (Objective Response by irRECIST) to PD-L1 Status (CPS =1)	Immune-related ORR is defined as the percentage of patients achieving a irCR or irPR based on irRECIST criteria. PD-L1 positivity was defined as Combined Positive Score =1. Evaluated objective response in PD-L1 positive patients; Per irRECIST: Immune-related (ir) Complete Response (irCR), disappearance of all target and non-target lesions, nodal short axis diameter <10 mm, no new lesions; irPartial Response (irPR), decrease of =30% in tumor burden relative to baseline, non-unequivocal progression of non-target lesions, no new lesions.	Baseline and every 9 weeks thereafter. After 6 months, every 12 weeks at the physician's discretion, if patient has had CR, PR, or SD > 27 weeks, an average of 4 years.
Secondary	Number of Patients Who Experienced Treatment-related Adverse Event (TRAE)	Per protocol, the number and percentage of patients with any treatment-related AE was summarized for all study patients combined. Patients were monitored for AE from the first day of administration of study medication through 30 days following last dose. Each AE (as defined by NCI CTCAE v4.03) was counted only once for a given subject. In the event a patient experienced repeated episodes of the same AE, then the event with the highest severity and/or strongest causal relationship to study treatment was used for purposes of tabulations.	First day of administration of study medication through 30 days following last dose, an average of 4 years.
Secondary	Objective Response Rate (ORR) Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	ORR is defined as the percentage of patients achieving a complete response (CR) or partial response (PR) based on RECIST 1.1 criteria.	Baseline and every 9 weeks thereafter. After 6 months, every 12 weeks at the physician's discretion, if patient has had CR, PR, or SD > 27 weeks, an average of 4 years.
Secondary	Clinical Benefit Rate (CBR) Using RECIST v1.1	CBR is defined as the percentage of patients achieving a CR or PR, or stable disease (SD) =4 months based on RECIST 1.1 criteria.	Baseline and every 9 weeks thereafter. After 6 months, every 12 weeks at the physician's discretion, if patient has had CR, PR, or SD > 27 weeks, an average of 4 years.
Secondary	Progression-free Survival (PFS) Using RECIST v1.1	PFS was defined as the time from administration of the first dose to the first documented disease progression according to RECIST v1.1 or death due to any cause, whichever occurs first. Patients who were alive and had not experienced disease progression at the time of data cutoff were censored.	Baseline and every 9 weeks thereafter. After 6 months, every 12 weeks at the physician's discretion, if patient has had CR, PR, or SD > 27 weeks, an average of 4 years.
Secondary	Immune-related ORR Using Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)	Immune-related ORR is defined as the percentage of patients achieving a irCR or irPR based on irRECIST criteria.	Baseline and every 9 weeks thereafter. After 6 months, every 12 weeks at the physician's discretion, if patient has had CR, PR, or SD > 27 weeks, an average of 4 years.
Secondary	Immune-related Clinical Benefit Rate (CBR) Using irRECIST	Immune-related CBR is defined as the percentage of patients achieving a irCR or irPR, or irSD =4 months based on irRECIST criteria	First day of administration of study medication through 30 days following last dose, an average of 4 years.
Secondary	Immune-related Progression-free Survival (PFS) Using irRECIST	Immune-related PFS was defined as the time from administration of the first dose to the first documented disease progression according to irRECIST or death due to any cause, whichever occurs first. Patients who were alive and had not experienced disease progression at the time of data cutoff were censored.	Baseline and every 9 weeks thereafter. After 6 months, every 12 weeks at the physician's discretion, if patient has had CR, PR, or SD > 27 weeks.

External Links

•   MD Anderson Cancer Center Website