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Sintilimab in Cancer of Unknown Primary

Primary Purpose

Cancer of Unknown Primary Site

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sintilimab
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cancer of Unknown Primary Site

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Has histopathologically confirmed unresectable, locally advanced, recurrent or metastatic CUP. Patients must have undergone standard work-up to attempt to identify the primary tumor prior to enrollment.
  2. Is refractory or intolerant to at least one line of systemic chemotherapy. Patient ineligible for cytotoxic chemotherapy due to contraindications will be eligible.
  3. Has an ECOG PS of 0 - 2.
  4. Must be unsuitable for definitive treatment, such as definitive chemoradiotherapy and/or surgery. For subjects who have received (neo)adjuvant or definitive chemotherapy/chemoradiotherapy, time from the completion of last treatment to disease recurrence must be > 3 months.
  5. Is able to provide archival or fresh tissues for correlative analysis with obtainable results.
  6. Has at least one measurable lesion as per RECIST v1.1.
  7. Has adequate organ and bone marrow functions, as defined below:

    • Complete blood count: absolute neutrophil count (ANC) ≥ 1.0 × 109/L, platelet (PLT) count ≥ 75 × 109/L, hemoglobin (HGB) ≥ 9.0 g/dL. Note: Subjects cannot receive blood transfusion, erythropoietin (EPO), or Granulocyte-colony stimulating factor (GSF) within 7 days prior to the blood collection.
    • Hepatic function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN in subjects without hepatic metastasis; TBIL ≤ 1.5 × ULN, ALT and AST ≤ 5 × ULN in subjects with hepatic metastasis.

    Exception: Patients with known Gilbert disease: serum bilirubin level ≤ 3 × ULN.

    • Renal function: urine protein < 2+ from random sample or < 1 g from 24-hour urine collection, and creatinine clearance rate (CrCl) ≥ 30 mL/min by Cockcroft-Gault formula:
    • Female: CrCl=((140-age)×weight(kg)×0.85)/(72×serum creatinine(mg/dL))
    • Male: CrCl=((140-age)×weight(kg)×1.00)/(72×serum creatinine(mg/dL))
  8. Adequate coagulation function, defined as international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; if the subject is receiving anticoagulant therapy, the results of coagulation tests need to be within the acceptable range for anticoagulants.
  9. Is expected to survive ≥ 12 weeks.
  10. Subject (female subjects of childbearing age or male subjects whose partners are of childbearing age) must take effective contraceptive measures during the entire course of the trial and until 180 days after the last dose (see Section 4.3).
  11. Is able to sign the informed consent form (ICF) and is able to comply with the scheduled follow-up visits and related procedures required in the protocol.

Exclusion Criteria:

  1. Has received treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug that specifically targets T-cell co-stimulation or immune checkpoint pathways.
  2. Is enrolled in another interventional clinical study. Current enrollment in an observational study (non-interventional) or in the follow-up phase of an interventional study is allowed.
  3. Has received palliative therapy for a local lesion within 2 weeks prior to the first dose.
  4. Has received systemic treatment with Chinese traditional medicines with anti-cancer indications or immunomodulators (including thymosins, interferons, and interleukins) within 2 weeks prior to the first dose of study treatment.
  5. Has received systemic immunosuppressants within 2 weeks. Allowed are local use of glucocorticoids administered by nasal, inhaled, or other routes, and systemic glucocorticoids at physiological doses (no more than 10 mg/day of prednisone or equivalents), or glucocorticoids to prevent allergies to contrast media.
  6. Has received a live attenuated vaccine within 4 weeks prior to the first dose of study treatment or is scheduled to receive live attenuated vaccine during the study period.

    Note: Seasonal inactivated influenza virus vaccines within 4 weeks prior to the first dose of study treatment are permitted, but attenuated influenza vaccines are not.

  7. Has undergone major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose of study treatment or is scheduled to receive major surgery during the course of the trial.
  8. Has any toxicity (excluding alopecia, events that are not clinically significant, or asymptomatic laboratory abnormalities) due to prior anti-tumor therapy that has not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 grade 0 or 1 prior to the first dose of study treatment.
  9. Has known symptomatic central nervous system (CNS) metastasis or carcinomatous meningitis. Subjects with brain metastases who have received prior treatment can be enrolled if the disease is stable (no imaging evidence of PD for at least 4 weeks prior to the first dose of study treatment), there is no evidence of new brain metastases or progression of the existing metastatic lesion(s) upon repeated imaging, and corticosteroids have not been required for at least 14 days prior to the first dose of study treatment. Patients with carcinomatous meningitis are ineligible, regardless of whether the disease is clinically stable or not.
  10. Has bone metastases and is at risk for paraplegia.
  11. Has known active autoimmune disease requiring treatment or a previous autoimmune disease history within 2 years (subjects with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment, hypothyroidism only requiring thyroid replacement, or type I diabetes only requiring insulin can be enrolled).
  12. Has a known history of primary immunodeficiency diseases.
  13. Has a known active pulmonary tuberculosis.
  14. Has a known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
  15. Is human immunodeficiency virus (HIV)-infected (has positive anti-HIV antibody).
  16. Has an active or poorly controlled serious infections.
  17. Has symptomatic congestive heart failure (NYHA Class II-IV) or symptomatic or poorly controlled arrhythmia.
  18. Has uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) despite standard treatment.
  19. Had any arterial thromboembolic event within 6 months prior to enrollment, including myocardial infarction, unstable angina, cerebrovascular accident, or transient cerebral ischemic attack.
  20. Has significant malnutrition, such as those requiring continuous parenteral nutrition ≥7 days. Allowed are those who received intravenous treatment for malnutrition that ended more than 4 weeks before the first dose of study treatment.
  21. Has a history of clinically significant deep venous thrombosis, pulmonary embolism, or other serious thromboembolic events within 3 months prior to enrollment (having an implantable port or catheter-related thrombosis or incidental pulmonary embolism detected on scan without symptoms or superficial venous thrombosis is not considered to be a "serious" thromboembolisms).
  22. Has uncontrolled metabolic disorders, non-malignant organ or systemic diseases, or cancer-related secondary diseases that may lead to higher medical risks and/or survival evaluation uncertainties.
  23. Has severe pulmonary dysfunction.
  24. Has hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh Class B or C.
  25. Has bowel obstruction or history of any of the following diseases: inflammatory bowel disease, extensive bowel resection (partial colectomy or extensive small intestine resection accompanied with chronic diarrhea), Crohn's disease, or ulcerative colitis.
  26. Has known acute or chronic active hepatitis B (positive HBsAg and hepatitis B (HBV) DNA viral load ≥ 103 copies/mL or > 200 IU/mL), or acute or chronic active hepatitis C (positive hepatitis C [HCV] antibody and detectable HCV RNA).
  27. Has history of gastrointestinal (GI) perforation and/or fistula within 6 months prior to study enrollment (having a gastrostomy or enterostomy is allowed).
  28. Has interstitial lung disease requiring corticosteroids.
  29. Has history of other primary malignant tumors, excluding:

    • Malignant tumors that achieved a complete response (CR) at least 2 years prior to enrollment and expected to require no treatment during the trial.
    • Adequately treated nonmelanoma skin cancer or lentigo maligna with no sign of disease recurrence.
    • Adequately treated carcinoma in situ with no sign of disease recurrence.
    • Prostate cancer, CLL or other cancers where the indolent nature of tumor allows for and patient is under active surveillance.
  30. Is pregnant or breastfeeding.
  31. Has an acute or chronic diseases, psychiatric disorders, or laboratory abnormality that may lead to the following consequences: increased investigational drug-related risks, or interference with interpretation of trial results, or is otherwise considered ineligible for participating in the trial by the investigators.

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (sintilimab)

Arm Description

The study drug is sintilimab. The first dose of study treatment should start on Day 1 of Cycle 1. For the rest of the treatment cycles, the study treatment can be administered 3 day before or 3 days after the scheduled day of administration. Treatment can be delayed for up to 1 week if the administration day is on a holiday or if the subject is otherwise unavailable.

Outcomes

Primary Outcome Measures

Objective response rate (ORR) [Efficacy]

Secondary Outcome Measures

Number of participants with Treatment-Emergent Adverse Events [Safety]
Disease control rate (DCR)
Duration of response (DOR)
Progression-free survival (PFS)
Overall survival (OS)
Quality of Life (QOL) Questionnaire

Full Information

First Posted
August 19, 2021
Last Updated
August 23, 2023
Sponsor
M.D. Anderson Cancer Center
Collaborators
Innovent Biologics (Suzhou) Co. Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT05024968
Brief Title
Sintilimab in Cancer of Unknown Primary
Official Title
A Phase 2 Clinical Trial Evaluating the Efficacy and Safety of Sintilimab for Advanced Rare Cancers (SiARa Cancer Study) - Cancer of Unknown Primary (SiARa-CUP)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 26, 2021 (Actual)
Primary Completion Date
January 2, 2024 (Anticipated)
Study Completion Date
January 2, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
Innovent Biologics (Suzhou) Co. Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase 2 clinical trial evaluating the efficacy and safety of sintilimab in subjects with CUP. Up to 45 subjects with CUP will be enrolled. Subjects will be treated with sintilimab at 200 mg via intravenous (IV) administration on Cycle 1 Day 1. The treatment will repeat every 3 weeks until progressive disease (PD), intolerable toxicity, initiation of new anti-tumor therapy, withdrawal of consent, lost to follow-up, death, completion of therapy, or any other investigator-determined reasons for treatment discontinuation (whichever occurs first). Treatment will continue for a maximum period of 24 months (starting from the first dose). During the trial, tumor imaging evaluation will be initially performed once every 9 weeks (± 7 days) and will be based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. After the completion or discontinuation of the study treatment, safety follow-up and survival follow-up will be performed. Considering the rareness of the disease, the patient accrual rate is expected to be approximately 2 patients per month. The total study duration is expected to be between 24-27 months with 6-month follow up.
Detailed Description
Primary Objectives: To evaluate the safety and efficacy of sintilimab in subjects with CUP Secondary Objectives: To evaluate the overall objective response rate (ORR) (investigator assessed), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and Quality of Life (QOL) on sintilimab in subjects with CUP Exploratory Objectives: To evaluate the correlation between biomarkers in tumor tissue and efficacy, including but not restricted to PD-L1 expression level, transcriptome sequencing, single-cell sequencing, and multicolor immunohistochemistry (IHC) analyses; To evaluate the correlation between biomarkers in peripheral blood and drug efficacy, including but not restricted to soluble PD-L1, circulating tumor DNA (ctDNA), and cytokine analyses.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer of Unknown Primary Site

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (sintilimab)
Arm Type
Experimental
Arm Description
The study drug is sintilimab. The first dose of study treatment should start on Day 1 of Cycle 1. For the rest of the treatment cycles, the study treatment can be administered 3 day before or 3 days after the scheduled day of administration. Treatment can be delayed for up to 1 week if the administration day is on a holiday or if the subject is otherwise unavailable.
Intervention Type
Drug
Intervention Name(s)
Sintilimab
Intervention Description
Given by IV
Primary Outcome Measure Information:
Title
Objective response rate (ORR) [Efficacy]
Time Frame
Within 4 cycles of treatment (1 cycles equals 28 days)
Secondary Outcome Measure Information:
Title
Number of participants with Treatment-Emergent Adverse Events [Safety]
Time Frame
From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year
Title
Disease control rate (DCR)
Time Frame
Up to 2 years
Title
Duration of response (DOR)
Time Frame
Time from response till progression, relapse/refractory, or death, assessed up to 2 years
Title
Progression-free survival (PFS)
Time Frame
Time interval between treatment start until disease progression, relapse/refractory, or death due to any cause, assessed up to 2 years
Title
Overall survival (OS)
Time Frame
Time interval between treatment start until death due to any cause, assessed up to 2 years
Title
Quality of Life (QOL) Questionnaire
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Has histopathologically confirmed unresectable, locally advanced, recurrent or metastatic CUP. Patients must have undergone standard work-up to attempt to identify the primary tumor prior to enrollment. Is refractory or intolerant to at least one line of systemic chemotherapy. Patient ineligible for cytotoxic chemotherapy due to contraindications will be eligible. Has an ECOG PS of 0 - 2. Must be unsuitable for definitive treatment, such as definitive chemoradiotherapy and/or surgery. For subjects who have received (neo)adjuvant or definitive chemotherapy/chemoradiotherapy, time from the completion of last treatment to disease recurrence must be > 3 months. Is able to provide archival or fresh tissues for correlative analysis with obtainable results. Has at least one measurable lesion as per RECIST v1.1. Has adequate organ and bone marrow functions, as defined below: Complete blood count: absolute neutrophil count (ANC) ≥ 1.0 × 109/L, platelet (PLT) count ≥ 75 × 109/L, hemoglobin (HGB) ≥ 9.0 g/dL. Note: Subjects cannot receive blood transfusion, erythropoietin (EPO), or Granulocyte-colony stimulating factor (GSF) within 7 days prior to the blood collection. Hepatic function: total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN in subjects without hepatic metastasis; TBIL ≤ 1.5 × ULN, ALT and AST ≤ 5 × ULN in subjects with hepatic metastasis. Exception: Patients with known Gilbert disease: serum bilirubin level ≤ 3 × ULN. Renal function: urine protein < 2+ from random sample or < 1 g from 24-hour urine collection, and creatinine clearance rate (CrCl) ≥ 30 mL/min by Cockcroft-Gault formula: Female: CrCl=((140-age)×weight(kg)×0.85)/(72×serum creatinine(mg/dL)) Male: CrCl=((140-age)×weight(kg)×1.00)/(72×serum creatinine(mg/dL)) Adequate coagulation function, defined as international normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 × ULN; if the subject is receiving anticoagulant therapy, the results of coagulation tests need to be within the acceptable range for anticoagulants. Is expected to survive ≥ 12 weeks. Subject (female subjects of childbearing age or male subjects whose partners are of childbearing age) must take effective contraceptive measures during the entire course of the trial and until 180 days after the last dose (see Section 4.3). Is able to sign the informed consent form (ICF) and is able to comply with the scheduled follow-up visits and related procedures required in the protocol. Exclusion Criteria: Has received treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug that specifically targets T-cell co-stimulation or immune checkpoint pathways. Is enrolled in another interventional clinical study. Current enrollment in an observational study (non-interventional) or in the follow-up phase of an interventional study is allowed. Has received palliative therapy for a local lesion within 2 weeks prior to the first dose. Has received systemic treatment with Chinese traditional medicines with anti-cancer indications or immunomodulators (including thymosins, interferons, and interleukins) within 2 weeks prior to the first dose of study treatment. Has received systemic immunosuppressants within 2 weeks. Allowed are local use of glucocorticoids administered by nasal, inhaled, or other routes, and systemic glucocorticoids at physiological doses (no more than 10 mg/day of prednisone or equivalents), or glucocorticoids to prevent allergies to contrast media. Has received a live attenuated vaccine within 4 weeks prior to the first dose of study treatment or is scheduled to receive live attenuated vaccine during the study period. Note: Seasonal inactivated influenza virus vaccines within 4 weeks prior to the first dose of study treatment are permitted, but attenuated influenza vaccines are not. Has undergone major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose of study treatment or is scheduled to receive major surgery during the course of the trial. Has any toxicity (excluding alopecia, events that are not clinically significant, or asymptomatic laboratory abnormalities) due to prior anti-tumor therapy that has not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 grade 0 or 1 prior to the first dose of study treatment. Has known symptomatic central nervous system (CNS) metastasis or carcinomatous meningitis. Subjects with brain metastases who have received prior treatment can be enrolled if the disease is stable (no imaging evidence of PD for at least 4 weeks prior to the first dose of study treatment), there is no evidence of new brain metastases or progression of the existing metastatic lesion(s) upon repeated imaging, and corticosteroids have not been required for at least 14 days prior to the first dose of study treatment. Patients with carcinomatous meningitis are ineligible, regardless of whether the disease is clinically stable or not. Has bone metastases and is at risk for paraplegia. Has known active autoimmune disease requiring treatment or a previous autoimmune disease history within 2 years (subjects with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment, hypothyroidism only requiring thyroid replacement, or type I diabetes only requiring insulin can be enrolled). Has a known history of primary immunodeficiency diseases. Has a known active pulmonary tuberculosis. Has a known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation. Is human immunodeficiency virus (HIV)-infected (has positive anti-HIV antibody). Has an active or poorly controlled serious infections. Has symptomatic congestive heart failure (NYHA Class II-IV) or symptomatic or poorly controlled arrhythmia. Has uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) despite standard treatment. Had any arterial thromboembolic event within 6 months prior to enrollment, including myocardial infarction, unstable angina, cerebrovascular accident, or transient cerebral ischemic attack. Has significant malnutrition, such as those requiring continuous parenteral nutrition ≥7 days. Allowed are those who received intravenous treatment for malnutrition that ended more than 4 weeks before the first dose of study treatment. Has a history of clinically significant deep venous thrombosis, pulmonary embolism, or other serious thromboembolic events within 3 months prior to enrollment (having an implantable port or catheter-related thrombosis or incidental pulmonary embolism detected on scan without symptoms or superficial venous thrombosis is not considered to be a "serious" thromboembolisms). Has uncontrolled metabolic disorders, non-malignant organ or systemic diseases, or cancer-related secondary diseases that may lead to higher medical risks and/or survival evaluation uncertainties. Has severe pulmonary dysfunction. Has hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh Class B or C. Has bowel obstruction or history of any of the following diseases: inflammatory bowel disease, extensive bowel resection (partial colectomy or extensive small intestine resection accompanied with chronic diarrhea), Crohn's disease, or ulcerative colitis. Has known acute or chronic active hepatitis B (positive HBsAg and hepatitis B (HBV) DNA viral load ≥ 103 copies/mL or > 200 IU/mL), or acute or chronic active hepatitis C (positive hepatitis C [HCV] antibody and detectable HCV RNA). Has history of gastrointestinal (GI) perforation and/or fistula within 6 months prior to study enrollment (having a gastrostomy or enterostomy is allowed). Has interstitial lung disease requiring corticosteroids. Has history of other primary malignant tumors, excluding: Malignant tumors that achieved a complete response (CR) at least 2 years prior to enrollment and expected to require no treatment during the trial. Adequately treated nonmelanoma skin cancer or lentigo maligna with no sign of disease recurrence. Adequately treated carcinoma in situ with no sign of disease recurrence. Prostate cancer, CLL or other cancers where the indolent nature of tumor allows for and patient is under active surveillance. Is pregnant or breastfeeding. Has an acute or chronic diseases, psychiatric disorders, or laboratory abnormality that may lead to the following consequences: increased investigational drug-related risks, or interference with interpretation of trial results, or is otherwise considered ineligible for participating in the trial by the investigators.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Alma DeLaGarza
Phone
713-792-5111
Email
adelagarza@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kanwal Raghav
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alma Delagarza
Phone
713-792-5111
Email
adelagarza@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Kanwal Raghav

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
M D Anderson Cancer Center

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Sintilimab in Cancer of Unknown Primary

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