Clinical Trials /

Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

NCT02834013

Description:

This phase II trial studies nivolumab and ipilimumab in treating patients with rare tumors. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial enrolls participants for the following cohorts based on condition: 1. Epithelial tumors of nasal cavity, sinuses, nasopharynx: A) Squamous cell carcinoma with variants of nasal cavity, sinuses, and nasopharynx and trachea (excluding laryngeal, nasopharyngeal cancer [NPC], and squamous cell carcinoma of the head and neck [SCCHN]) B) Adenocarcinoma and variants of nasal cavity, sinuses, and nasopharynx (closed to accrual 07/27/2018) 2. Epithelial tumors of major salivary glands (closed to accrual 03/20/2018) 3. Salivary gland type tumors of head and neck, lip, esophagus, stomach, trachea and lung, breast and other location (closed to accrual) 4. Undifferentiated carcinoma of gastrointestinal (GI) tract 5. Adenocarcinoma with variants of small intestine (closed to accrual 05/10/2018) 6. Squamous cell carcinoma with variants of GI tract (stomach small intestine, colon, rectum, pancreas) (closed to accrual 10/17/2018) 7. Fibromixoma and low grade mucinous adenocarcinoma (pseudomixoma peritonei) of the appendix and ovary (closed to accrual 03/20/2018) 8. Rare pancreatic tumors including acinar cell carcinoma, mucinous cystadenocarcinoma or serous cystadenocarcinoma. Pancreatic adenocarcinoma is not eligible 9. Intrahepatic cholangiocarcinoma (closed to accrual 03/20/2018) 10. Extrahepatic cholangiocarcinoma and bile duct tumors (closed to accrual 03/20/2018) 11. Sarcomatoid carcinoma of lung 12. Bronchoalveolar carcinoma lung. This condition is now also referred to as adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma, or invasive mucinous adenocarcinoma 13. Non-epithelial tumors of the ovary: A) Germ cell tumor of ovary B) Mullerian mixed tumor and adenosarcoma (closed to accrual 03/30/2018) 14. Trophoblastic tumor: A) Choriocarcinoma (closed to accrual) 15. Transitional cell carcinoma other than that of the renal, pelvis, ureter, or bladder (closed to accrual) 16. Cell tumor of the testes and extragonadal germ tumors: A) Seminoma and testicular sex cord cancer B) Non seminomatous tumor C) Teratoma with malignant transformation (closed to accrual) 17. Epithelial tumors of penis - squamous adenocarcinoma cell carcinoma with variants of penis 18. Squamous cell carcinoma variants of the genitourinary (GU) system 19. Spindle cell carcinoma of kidney, pelvis, ureter 20. Adenocarcinoma with variants of GU system (excluding prostate cancer) (closed to accrual 07/27/2018) 21. Odontogenic malignant tumors 22. Pancreatic neuroendocrine tumor (PNET) (formerly named: Endocrine carcinoma of pancreas and digestive tract.) (closed to accrual) 23. Neuroendocrine carcinoma including carcinoid of the lung (closed to accrual 12/19/2017) 24. Pheochromocytoma, malignant (closed to accrual) 25. Paraganglioma (closed to accrual 11/29/2018) 26. Carcinomas of pituitary gland, thyroid gland parathyroid gland and adrenal cortex (closed to accrual) 27. Desmoid tumors 28. Peripheral nerve sheath tumors and NF1-related tumors (closed to accrual 09/19/2018) 29. Malignant giant cell tumors 30. Chordoma (closed to accrual 11/29/2018) 31. Adrenal cortical tumors (closed to accrual 06/27/2018) 32. Tumor of unknown primary (Cancer of Unknown Primary; CuP) (closed to accrual 12/22/2017) 33. Not Otherwise Categorized (NOC) Rare Tumors [To obtain permission to enroll in the NOC cohort, contact: S1609SC@swog.org] (closed to accrual 03/15/2019) 34. Adenoid cystic carcinoma (closed to accrual 02/06/2018) 35. Vulvar cancer (temporarily closed to accrual) 36. MetaPLASTIC carcinoma (of the breast) (closed to accrual) 37. Gastrointestinal stromal tumor (GIST) (closed to accrual 09/26/2018) 38. Perivascular epithelioid cell tumor (PEComa) 39. Apocrine tumors/extramammary Paget's disease (closed to accrual) 40. Peritoneal mesothelioma (temporarily closed to accrual 05/08/2020) 41. Basal cell carcinoma (temporarily closed to accrual 04/29/2020) 42. Clear cell cervical cancer 43. Esthenioneuroblastoma (closed to accrual) 44. Endometrial carcinosarcoma (malignant mixed Mullerian tumors) (closed to accrual) 45. Clear cell ovarian cancer (closed to accrual) 46. Gestational trophoblastic disease (GTD) 47. Gallbladder cancer 48. Small cell carcinoma of the ovary, hypercalcemic type 49. PD-L1 amplified tumors 50. Angiosarcoma 51. High-grade neuroendocrine carcinoma (pancreatic neuroendocrine tumor [PNET] should be enrolled in Cohort 22; prostatic neuroendocrine carcinomas should be enrolled into Cohort 52). Small cell lung cancer is not eligible (temporarily closed to accrual 03/25/2020) 52. Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC)

Related Conditions:
  • Angiosarcoma
  • Bladder Squamous Cell Carcinoma
  • Bronchioloalveolar Carcinoma
  • Cervical Clear Cell Adenocarcinoma
  • Desmoid-Type Fibromatosis
  • Esophageal Undifferentiated Carcinoma
  • Gallbladder Carcinoma
  • Gestational Trophoblastic Tumor
  • Lung Sarcomatoid Carcinoma
  • Malignant Giant Cell Neoplasm
  • Malignant Odontogenic Neoplasm
  • Malignant Solid Tumor
  • Mucinous Tubular and Spindle Cell Carcinoma of the Kidney
  • Ovarian Small Cell Carcinoma, Hypercalcemic Type
  • PEComa
  • Pancreatic Acinar Cell Carcinoma
  • Pancreatic Cystadenocarcinoma
  • Pancreatic Serous Cystadenocarcinoma
  • Penile Carcinoma
  • Prostate Small Cell Carcinoma
  • Prostate Squamous Cell Carcinoma
  • Renal Pelvis Squamous Cell Carcinoma
  • Small Intestinal Undifferentiated Carcinoma
  • Squamous Cell Carcinoma of the Penis
  • Undifferentiated Gastric Carcinoma
  • Ureter Squamous Cell Carcinoma
  • Urethral Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
  • Official Title: DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01041
  • SECONDARY ID: NCI-2016-01041
  • SECONDARY ID: S1609
  • SECONDARY ID: S1609
  • SECONDARY ID: S1609
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT02834013

Conditions

  • Acinar Cell Carcinoma
  • Adenoid Cystic Carcinoma
  • Adrenal Cortex Carcinoma
  • Adrenal Gland Pheochromocytoma
  • Anal Canal Neuroendocrine Carcinoma
  • Anal Canal Undifferentiated Carcinoma
  • Angiosarcoma
  • Apocrine Neoplasm
  • Appendix Mucinous Adenocarcinoma
  • Bartholin Gland Transitional Cell Carcinoma
  • Basal Cell Carcinoma
  • Bladder Adenocarcinoma
  • Cervical Adenocarcinoma
  • Cervical Clear Cell Adenocarcinoma
  • Cholangiocarcinoma
  • Chordoma
  • Colorectal Squamous Cell Carcinoma
  • Desmoid-Type Fibromatosis
  • Endometrial Transitional Cell Carcinoma
  • Endometrioid Adenocarcinoma
  • Esophageal Neuroendocrine Carcinoma
  • Esophageal Undifferentiated Carcinoma
  • Extrahepatic Bile Duct Carcinoma
  • Extramammary Paget Disease
  • Fallopian Tube Adenocarcinoma
  • Fallopian Tube Transitional Cell Carcinoma
  • Fibromyxoid Tumor
  • Gallbladder Carcinoma
  • Gastric Neuroendocrine Carcinoma
  • Gastric Squamous Cell Carcinoma
  • Gastric Undifferentiated Carcinoma
  • Gastrointestinal Stromal Tumor
  • Gestational Trophoblastic Tumor
  • Giant Cell Carcinoma
  • Intestinal Neuroendocrine Carcinoma
  • Intrahepatic Cholangiocarcinoma
  • Lung Carcinoid Tumor
  • Lung Sarcomatoid Carcinoma
  • Major Salivary Gland Carcinoma
  • Malignant Odontogenic Neoplasm
  • Malignant Peripheral Nerve Sheath Tumor
  • Malignant Solid Neoplasm
  • Malignant Testicular Sex Cord-Stromal Tumor
  • Metaplastic Breast Carcinoma
  • Metastatic Malignant Neoplasm of Unknown Primary
  • Minimally Invasive Lung Adenocarcinoma
  • Mixed Mesodermal (Mullerian) Tumor
  • Mucinous Adenocarcinoma
  • Mucinous Cystadenocarcinoma
  • Nasal Cavity Adenocarcinoma
  • Nasal Cavity Carcinoma
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Papillary Adenocarcinoma
  • Nasopharyngeal Undifferentiated Carcinoma
  • Oral Cavity Carcinoma
  • Oropharyngeal Undifferentiated Carcinoma
  • Ovarian Adenocarcinoma
  • Ovarian Germ Cell Tumor
  • Ovarian Mucinous Adenocarcinoma
  • Ovarian Squamous Cell Carcinoma
  • Ovarian Transitional Cell Carcinoma
  • Pancreatic Acinar Cell Carcinoma
  • Pancreatic Neuroendocrine Carcinoma
  • Paraganglioma
  • Paranasal Sinus Adenocarcinoma
  • Paranasal Sinus Carcinoma
  • Parathyroid Gland Carcinoma
  • PEComa
  • Peritoneal Mesothelioma
  • Pituitary Gland Carcinoma
  • Placental Choriocarcinoma
  • Primary Peritoneal High Grade Serous Adenocarcinoma
  • Pseudomyxoma Peritonei
  • Rare Disorder
  • Scrotal Squamous Cell Carcinoma
  • Seminal Vesicle Adenocarcinoma
  • Seminoma
  • Serous Cystadenocarcinoma
  • Small Intestinal Adenocarcinoma
  • Small Intestinal Squamous Cell Carcinoma
  • Spindle Cell Neoplasm
  • Squamous Cell Carcinoma of the Penis
  • Teratoma With Somatic-Type Malignancy
  • Testicular Non-Seminomatous Germ Cell Tumor
  • Thyroid Gland Carcinoma
  • Tracheal Carcinoma
  • Transitional Cell Carcinoma
  • Ureter Adenocarcinoma
  • Ureter Squamous Cell Carcinoma
  • Urethral Adenocarcinoma
  • Urethral Squamous Cell Carcinoma
  • Vaginal Adenocarcinoma
  • Vaginal Squamous Cell Carcinoma, Not Otherwise Specified
  • Vulvar Carcinoma

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm I (nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm I (nivolumab, ipilimumab)

Purpose

This phase II trial studies nivolumab and ipilimumab in treating patients with rare tumors. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial enrolls participants for the following cohorts based on condition: 1. Epithelial tumors of nasal cavity, sinuses, nasopharynx: A) Squamous cell carcinoma with variants of nasal cavity, sinuses, and nasopharynx and trachea (excluding laryngeal, nasopharyngeal cancer [NPC], and squamous cell carcinoma of the head and neck [SCCHN]) B) Adenocarcinoma and variants of nasal cavity, sinuses, and nasopharynx (closed to accrual 07/27/2018) 2. Epithelial tumors of major salivary glands (closed to accrual 03/20/2018) 3. Salivary gland type tumors of head and neck, lip, esophagus, stomach, trachea and lung, breast and other location (closed to accrual) 4. Undifferentiated carcinoma of gastrointestinal (GI) tract 5. Adenocarcinoma with variants of small intestine (closed to accrual 05/10/2018) 6. Squamous cell carcinoma with variants of GI tract (stomach small intestine, colon, rectum, pancreas) (closed to accrual 10/17/2018) 7. Fibromixoma and low grade mucinous adenocarcinoma (pseudomixoma peritonei) of the appendix and ovary (closed to accrual 03/20/2018) 8. Rare pancreatic tumors including acinar cell carcinoma, mucinous cystadenocarcinoma or serous cystadenocarcinoma. Pancreatic adenocarcinoma is not eligible 9. Intrahepatic cholangiocarcinoma (closed to accrual 03/20/2018) 10. Extrahepatic cholangiocarcinoma and bile duct tumors (closed to accrual 03/20/2018) 11. Sarcomatoid carcinoma of lung 12. Bronchoalveolar carcinoma lung. This condition is now also referred to as adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma, or invasive mucinous adenocarcinoma 13. Non-epithelial tumors of the ovary: A) Germ cell tumor of ovary B) Mullerian mixed tumor and adenosarcoma (closed to accrual 03/30/2018) 14. Trophoblastic tumor: A) Choriocarcinoma (closed to accrual) 15. Transitional cell carcinoma other than that of the renal, pelvis, ureter, or bladder (closed to accrual) 16. Cell tumor of the testes and extragonadal germ tumors: A) Seminoma and testicular sex cord cancer B) Non seminomatous tumor C) Teratoma with malignant transformation (closed to accrual) 17. Epithelial tumors of penis - squamous adenocarcinoma cell carcinoma with variants of penis 18. Squamous cell carcinoma variants of the genitourinary (GU) system 19. Spindle cell carcinoma of kidney, pelvis, ureter 20. Adenocarcinoma with variants of GU system (excluding prostate cancer) (closed to accrual 07/27/2018) 21. Odontogenic malignant tumors 22. Pancreatic neuroendocrine tumor (PNET) (formerly named: Endocrine carcinoma of pancreas and digestive tract.) (closed to accrual) 23. Neuroendocrine carcinoma including carcinoid of the lung (closed to accrual 12/19/2017) 24. Pheochromocytoma, malignant (closed to accrual) 25. Paraganglioma (closed to accrual 11/29/2018) 26. Carcinomas of pituitary gland, thyroid gland parathyroid gland and adrenal cortex (closed to accrual) 27. Desmoid tumors 28. Peripheral nerve sheath tumors and NF1-related tumors (closed to accrual 09/19/2018) 29. Malignant giant cell tumors 30. Chordoma (closed to accrual 11/29/2018) 31. Adrenal cortical tumors (closed to accrual 06/27/2018) 32. Tumor of unknown primary (Cancer of Unknown Primary; CuP) (closed to accrual 12/22/2017) 33. Not Otherwise Categorized (NOC) Rare Tumors [To obtain permission to enroll in the NOC cohort, contact: S1609SC@swog.org] (closed to accrual 03/15/2019) 34. Adenoid cystic carcinoma (closed to accrual 02/06/2018) 35. Vulvar cancer (temporarily closed to accrual) 36. MetaPLASTIC carcinoma (of the breast) (closed to accrual) 37. Gastrointestinal stromal tumor (GIST) (closed to accrual 09/26/2018) 38. Perivascular epithelioid cell tumor (PEComa) 39. Apocrine tumors/extramammary Paget's disease (closed to accrual) 40. Peritoneal mesothelioma (temporarily closed to accrual 05/08/2020) 41. Basal cell carcinoma (temporarily closed to accrual 04/29/2020) 42. Clear cell cervical cancer 43. Esthenioneuroblastoma (closed to accrual) 44. Endometrial carcinosarcoma (malignant mixed Mullerian tumors) (closed to accrual) 45. Clear cell ovarian cancer (closed to accrual) 46. Gestational trophoblastic disease (GTD) 47. Gallbladder cancer 48. Small cell carcinoma of the ovary, hypercalcemic type 49. PD-L1 amplified tumors 50. Angiosarcoma 51. High-grade neuroendocrine carcinoma (pancreatic neuroendocrine tumor [PNET] should be enrolled in Cohort 22; prostatic neuroendocrine carcinomas should be enrolled into Cohort 52). Small cell lung cancer is not eligible (temporarily closed to accrual 03/25/2020) 52. Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC)

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
      overall response rate (ORR) in subsets of patients with advanced rare cancers treated with
      ipilimumab plus nivolumab combination immunotherapy.

      II. To evaluate the overall response rate (ORR) in patients with gestational trophoblastic
      tumors treated with ipilimumab plus nivolumab combination immunotherapy.

      III. To evaluate the RECIST v1.1 overall response rate (ORR) in patients PD-L1 amplified
      cancers treated with nivolumab immunotherapy.

      SECONDARY OBJECTIVES:

      I. To evaluate toxicities in each cohort. II. To estimate overall survival (OS),
      progression-free survival (PFS), clinical benefit rate; and to estimate immune related
      (i)RECIST ORR (iORR), and iRECIST PFS (iPFS) across cohorts and within each cohort.

      OUTLINE: Patients are assigned to 1 of 2 arms.

      ARM I (ALL COHORTS EXCEPT THE PD-L1 AMPLIFIED COHORT): Patients receive nivolumab
      intravenously (IV) over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on
      day 1. Treatment repeats every 42 days for up to 17 cycles (2 years) in the absence of
      disease progression or unacceptable toxicity. Patients who complete 17 cycles (2 years) of
      therapy, may continue receiving the same treatment with nivolumab and ipilimumab, or receive
      nivolumab once every 14 or 28 days (2 weeks or 4 weeks) per physician discretion in the
      absence of disease progression or unacceptable toxicity. Patients who stop treatment prior to
      the completion of 17 cycles of therapy may receive nivolumab once every 14 or 28 days (2
      weeks or 4 weeks) in the absence of disease progression or unacceptable toxicity.

      ARM II (PD-L1 AMPLIFIED COHORT): Patients receive nivolumab IV over 30 minutes on days 1, 15
      and 29. Treatment repeats every 42 days for up to 17 cycles (2 years) in the absence of
      disease progression or unacceptable toxicity. After 17 cycles (2 years) of therapy, patients
      may receive nivolumab once every 14 or 28 days (2 weeks or 4 weeks) in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 10 years from registration.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (nivolumab, ipilimumab)ExperimentalPatients receive nivolumab IV over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on day 1. Treatment repeats every 42 days for up to 17 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who complete 17 cycles (2 years) of therapy, may continue receiving the same treatment with nivolumab and ipilimumab, or receive nivolumab once every 14 or 28 days (2 weeks or 4 weeks) per physician discretion in the absence of disease progression or unacceptable toxicity. Patients who stop treatment prior to the completion of 17 cycles of therapy may receive nivolumab once every 14 or 28 days (2 weeks or 4 weeks) in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab
Arm II (nivolumab)ExperimentalPatients receive nivolumab IV over 30 minutes on days 1, 15 and 29. Treatment repeats every 42 days for up to 17 cycles (2 years) in the absence of disease progression or unacceptable toxicity. After 17 cycles (2 years) of therapy, patients may receive nivolumab once every 14 or 28 days (2 weeks or 4 weeks) in the absence of disease progression or unacceptable toxicity.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients are eligible under ONE of the following criteria:

               -  For all cohorts except the gestational trophoblastic disease (GTD) (Cohort #47),
                  patients must have histologically and/or biochemically confirmed rare cancer and
                  must be able to submit specimens; to be eligible for the GTD cohort: patients
                  must have disease confirmed by quantitative serum beta-human chorionic
                  gonadotropin (hCG) within 28 days prior to registration and must be able to
                  submit blood specimens (tissue submission is not required for patients who will
                  be registered to the GTD cohort [Cohort #47]); NOTE: Subsequent to site's
                  Institutional Review Board (IRB) approval of revision 3, patients are NOT
                  required to participate in EAY131 "National Cancer Institute (NCI)-Molecular
                  Analysis for Therapy Choice (MATCH)" to register to S1609 OR

               -  FOR PATIENTS WITH PD-L1 AMPLIFICATION (COHORT #50) ONLY: All solid tumors
                  (excluding lymphoma) are allowed for the PD-L1 amplified cohort if they have
                  PD-L1 amplification; patients may be considered for registration to the PD-L1
                  amplified cohort (Cohort #50) with the confirmation of at least one of the study
                  chairs; PD-L1 amplification is defined as having deoxyribonucleic acid (DNA) copy
                  number of equal to or greater than six by any of the following Clinical
                  Laboratory Improvement Act (CLIA)-approved lab; (Immunohisochemistry [IHC] and
                  fluorescence in situ hybridization [FISH] are not allowed); the assay must be
                  done at or after the diagnosis of advanced disease, but PRIOR TO REGISTRATION;
                  NOTE: patients with PD-L1 overexpression by IHC or PD-L1 amplification by FISH do
                  not quality for this cohort; OR

               -  FOR PATIENTS ENROLLED IN EAY131 "NCI-MATCH" PRIOR TO EAY131 ADDENDUM 10 ONLY:
                  Patients must have histologically confirmed rare cancer that did not have a match
                  to a molecularly-guided therapy on EAY131 "NCI-MATCH" protocol or who are off
                  protocol treatment on EAY131, "NCI-MATCH" and have no further molecularly-matched
                  treatment recommendations per EAY131, "NCI-MATCH" or who are otherwise unable to
                  receive EAY131, "NCI-MATCH" therapy

          -  Patients who do not qualify for one of the histologic cohorts and are not on the
             ineligible histology list may be considered for registration in the "Not Otherwise
             Categorized" Rare Tumors cohort with confirmation of at least one of the study chairs
             via email

               -  NOTE: The "Not Otherwise Categorized" Rare Tumors cohort was permanently closed
                  to accrual on 3/15/2019

          -  Patients who are determined to have a rare cancer with unknown primary site are
             eligible under cohort #32 (tumor of unknown primary [cancer of unknown primary; CuP]),
             provided that there is histologic documentation of metastatic malignancy with no
             discernible primary site identified from histopathologic review, physical exam and
             associated cross-sectional imaging of the chest, abdomen, and pelvis

               -  NOTE: The "Tumor of unknown primary (Cancer of Unknown Primary; CuP" cohort was
                  permanently closed to accrual on 12/22/2017

          -  Patients must also meet one of the following:

               -  Patients must have progressed following at least one line of standard systemic
                  therapy and there must not be other approved/standard therapy available that has
                  been shown to prolong overall survival (i.e. in a randomized trial against
                  another standard treatment or by comparison to historical controls); patients who
                  cannot receive other standard therapy that has been shown to prolonged survival
                  due to medical issues will be eligible, if other eligibility criteria are met; OR

               -  Patients for whose disease no standard treatment exists that has been shown to
                  prolong overall survival

          -  For all cohorts except the GTD cohort (Cohort #47): Patients must have a diagnostic
             quality computed tomography (CT) scan or magnetic resonance imaging (MRI), performed
             within 28 days prior to registration, which demonstrates measurable disease, as
             defined in RECIST v. 1.1; scans must include imaging of the chest, abdomen and pelvis,
             with the exception of patients with head/neck cancer, who must have imaging of the
             chest, abdomen, pelvis and neck; if there is clinical suspicion for bone metastases at
             the time of enrollment (in the judgement of the treating investigator) bone scan
             should be performed; bone scans done within 42 days prior to registration may be used
             to establish baseline condition at registration

          -  No other prior malignancy is allowed except for the following:

               -  Adequately managed stage I or II cancer from which the patient is currently in
                  complete remission

               -  Any other cancer from which the patient has been disease free for one year

               -  Adequately managed stage I or II follicular thyroid or prostate cancer is also
                  eligible, wherein patient is not required to be in complete remission

               -  Note: Second primary tumors are not allowed concurrent with any of the eligible
                  rare cancers

          -  For all cohorts except the PD-L1 amplified tumors cohort (Cohort # 50): Patients may
             have received either prior anti-CTLA4 or other prior anti-PD-1/anti-PD-L1 therapy, but
             not both, provided that it is completed >= 4 weeks prior to registration. To be
             eligible for the PD-L1 amplified tumors cohort (Cohort #50): Patients must not have
             received anti-PD-1/anti-PD-L1 therapy; prior anti-CTLA-4 is allowed provided that it
             is completed >= 4 weeks prior to registration

          -  Patients with clinically controlled thyroiditis or pituitary disorders on stable
             replacement therapy are eligible

          -  Patients with autoimmune disease who are otherwise eligible must not have received
             steroid and immunosuppressive therapy within 28 days prior to registration

          -  Patients with brain metastases or primary brain tumors must have completed treatment,
             surgery or radiation therapy >= 28 days prior to registration and have stable disease
             at time of registration; these patients must also have a CT or MRI of the brain to
             evaluate for CNS disease within 42 days prior to registration to S1609; metastatic
             brain parenchymal disease must have been treated and patient must be off steroids for
             7 days prior to registration

          -  Hormonal or endocrine blockade is permitted as long as patient has demonstrated
             progression on prior therapy (e.g. gonadotrophin releasing hormone [GnRH],
             somatostatin); long-acting somatostatin analogs (including octreotide) and androgen
             deprivation treatment (including long-acting leuprolide) are permitted while on
             protocol therapy

          -  Patients must have a Zubrod performance status of 0-2

          -  Absolute neutrophil count (ANC) >= 1,000/mcL (within 28 days prior to registration)

          -  Platelets >= 75,000/mcL (within 28 days prior to registration)

          -  Hemoglobin >= 8 g/dL (within 28 days prior to registration)

          -  Total bilirubin =< 2.0 x institutional upper limit of normal (IULN) or for
             documented/suspected Gilbert's disease, total bilirubin =< 3.0 x IULN (within 28 days
             prior to registration)

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 3 x IULN
             (within 28 days prior to registration)

          -  Serum creatinine =< 2.0 x IULN (within 28 days prior to registration)

          -  Creatinine clearance (CrCl) >= 50 mL/min., as estimated by the Cockcroft and Gault
             formula; estimated creatinine clearance is based on actual body weight (within 28 days
             prior to registration)

          -  Patients must have adequate thyroid function, as evidenced by either
             thyroid-stimulating hormone (TSH) or, free thyroxine (T4) serum tests demonstrating
             values within the normal range, within 28 days prior to registration; at
             pre-registration, if TSH is not within normal limits, then free T4 must be performed
             and must be within normal range for patient to be eligible; Note: TSH, with reflex T4
             (if TSH is abnormal) is allowable if per institutional standard, provided that free T4
             is within normal range; patients who have undergone thyroidectomy or who are on
             thyroid suppression for their cancer are not required to have normal TSH and free T4

          -  Patients must have adequate adrenal axis function, as evidenced by cortisol levels
             within institutional normal ranges (ante meridiem [AM] cortisol preferred), OR
             adrenocorticotropic hormone (ACTH) values within the institutional normal ranges
             within 28 days prior to registration; if cortisol levels are not within normal limits
             prior to registration, then ACTH must be performed and must be within normal ranges
             for patient to be eligible; Note: Neither cortisol nor ACTH levels are required for
             patients with primary adrenal tumors (e.g. adrenocortical carcinoma)

          -  For women of childbearing potential, the local investigator must rule out pregnancy;
             Except for Cohorts 13 and 47, where tumor types may express beta-hCG, women of
             childbearing potential must have a serum or urine pregnancy test within 7 days prior
             to registration; for Cohorts 13 and 47, where tumor types may produce hCG (e.g. germ
             cell tumors or trophoblastic disease), other pregnancy exclusion methods should be
             used to rule out pregnancy, such as ultrasound examination, documented history of
             effective contraception, or documented infertility; all females of childbearing
             potential must have been demonstrated not to be pregnant within 7 days prior to
             registration and agree to use birth control throughout study and for 23 weeks after
             completion of protocol therapy; patients must not be pregnant or nursing due to risk
             of fetal or nursing infant harm; women of childbearing potential must have agreed to
             use an effective contraceptive method; a woman is considered to be of "childbearing
             potential" if she has had menses at any time in the preceding 12 consecutive months;
             in addition to routine contraceptive methods, "effective contraception" also includes
             heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect
             of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or
             bilateral tubal ligation; however, if at any point a previously celibate patient
             chooses to become heterosexually active during the time period for use of
             contraceptive measures outlined in the protocol, she is responsible for beginning
             contraceptive measures

          -  Men of reproductive potential must have agreed to use birth control throughout the
             study and for 31 weeks after completion of protocol therapy; in addition to routine
             contraceptive methods, "effective contraception" also includes heterosexual celibacy
             and surgery intended to prevent pregnancy (vasectomy); however, if at any point a
             previously celibate patient chooses to become heterosexually active during the time
             period for use of contraceptive measures outlined in the protocol, he is responsible
             for beginning contraceptive measures

          -  Patients who are known to be human immunodeficiency virus (HIV)-positive at
             registration are eligible at the time of registration:

               -  CD4+ cell count greater or equal to 250 cells/mm^3

               -  No history of non-malignancy acquired immunodeficiency syndrome (AIDS)-defining
                  conditions other than historical low CD4+ cell counts

          -  Patients must have amylase or lipase within =< 1.5 x IULN without symptoms of
             pancreatitis at registration, within 28 days prior to registration

          -  Patients must have fully recovered from any adverse effects of major surgery (to =<
             grade 1) at least 14 days prior to registration

        Exclusion Criteria:

          -  Patients who had prior grade 3 or higher immune-related adverse event (e.g.
             pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer
             vaccine, cytokine, etc.) are not eligible

          -  Patients are not eligible if they have had or are planned for solid organ transplant

          -  Patients must not currently be receiving any other investigational agents or any other
             systemic anti-cancer therapy (including radiation, excluding RANKL inhibitors and
             bisphosphonates); in event patient recently received any other systemic anti-cancer
             therapy, patient must be off therapy at least 7 days prior to registration and any
             therapy-induced toxicity must have recovered to =< grade 1, except alopecia and =<
             grade 2 neuropathy which are allowed; any planned radiation therapy must be completed
             before registration to S1609

          -  Patients must not have prior history of allergy or known hypersensitivity to nivolumab
             or ipilimumab

          -  Patients must not have known active hepatitis B virus (HBV) or hepatitis virus (HCV)
             infection at time of registration; patients with HBV or HCV that have an undetectable
             viral load and no residual hepatic impairment are eligible

          -  Patients must not have active autoimmune disease that has required systemic treatment
             in past 2 years (i.e., with use of disease modifying agents, immunosuppressive drugs,
             or corticosteroids with prednisone dose >= 10 mg); replacement therapy (e.g.,
             thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
             pituitary insufficiency, etc.) is not considered a form of systemic treatment;
             autoimmune diseases include but are not limited to autoimmune hepatitis, inflammatory
             bowel disease (including ulcerative colitis and Crohn's disease), as well as
             symptomatic disease (e.g.: rheumatoid arthritis, systemic progressive sclerosis
             [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's
             granulomatosis]); central nervous system (CNS) or motor neuropathy considered of
             autoimmune origin (e.g., Guillain-Barre syndrome and Myasthenia gravis, multiple
             sclerosis or glomerulonephritis); vitiligo, alopecia, hypothyroidism on stable doses
             of thyroid replacement therapy, psoriasis not requiring systemic therapy within the
             past 2 years is permitted; short-term steroid premedication for contrast allergy is
             permitted

          -  Patients must not have any uncontrolled intercurrent illness including (not limited
             to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA]
             III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks
             prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of
             NCI Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4 grade >= 2),
             known psychiatric illness that would limit study compliance, intra-cardiac
             defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>=
             grade 3)

               -  Note: Patients with history of CHF or patients who are deemed at risk because of
                  underlying cardiovascular disease or exposure to cardiotoxic drugs should have an
                  electrocardiogram (EKG) and echocardiogram (ECHO), as clinically indicated, at
                  baseline and at the start of each cycle; patients who have evidence at baseline
                  (or subsequently) of CHF, myocardial infarction (MI), cardiomyopathy, or myositis
                  cardiac evaluation (NYHA I/II) should have additional consult by a cardiologist,
                  including review of EKG, creatine phosphokinase (CPK), troponin, echocardiogram,
                  as clinically indicated

          -  Patients must not have symptomatic interstitial lung disease or pneumonitis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 10 years
Safety Issue:
Description:Defined as confirmed and unconfirmed complete and partial response. Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 10 years
Safety Issue:
Description:Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Assuming 16 eligible patients per stratum, this will be sufficient to estimate each binary version of this endpoint within +/- 25% (95% confidence interval).
Measure:Best response
Time Frame:Up to 10 years
Safety Issue:
Description:Calculated from the sequence of RECIST 1.1 and immune-related (i)RECIST objectives. Assuming 16 eligible patients per stratum, this will be sufficient to estimate each binary version of this endpoint within +/- 25% (95% confidence interval).
Measure:Clinical benefit rate
Time Frame:6 months
Safety Issue:
Description:Defined as complete response, partial response, or stable disease, estimated using both RECIST and iRECIST. Assuming 16 eligible patients per stratum, this will be sufficient to estimate each binary version of this endpoint within +/- 25% (95% confidence interval).
Measure:Overall survival (OS)
Time Frame:From date of registration to date of death due to any cause, assessed up to 10 years
Safety Issue:
Description:Estimated using both RECIST and immune-related (ir) RESIST criteria (RC). Assuming 16 eligible patients per stratum, this will be sufficient to estimate each binary version of this endpoint within +/- 25% (95% confidence interval).
Measure:Progression free survival (PFS)
Time Frame:From date of registration to date of first documentation of progression or symptomatic deterioration or death, assessed up to 10 years
Safety Issue:
Description:Estimated using both RECIST and irRC. Assuming 16 eligible patients per stratum, this will be sufficient to estimate each binary version of this endpoint within +/- 25% (95% confidence interval).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 13, 2020