Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
Nivolumab and Ipilimumab in Treating Patients With Rare Tumors
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 (closed to accrual)

 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 (closed to accrual)

 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 (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

 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 endometrial cancer

 46. Clear cell ovarian cancer (closed to accrual)

 47. Gestational trophoblastic disease (GTD)

 48. Gallbladder cancer

 49. Small cell carcinoma of the ovary, hypercalcemic type

 50. PD-L1 amplified tumors

 51. Angiosarcoma

 52. High-grade neuroendocrine carcinoma (pancreatic neuroendocrine tumor [PNET] should be
 enrolled in Cohort 22; prostatic neuroendocrine carcinomas should be enrolled into
 Cohort 53). Small cell lung cancer is not eligible (closed to accrual)

 53. Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC)
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.
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