Nivolumab and Ipilimumab in Treating Patients With Rare Tumors

Study Description

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Brief Summary:

This clinical trial studies nivolumab and ipilimumab in treating patients with rare tumors. Monoclonal antibodies, such as nivolumab and ipilimumab, 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.
2. Epithelial tumors of major salivary glands
3. Salivary gland type tumors of head and neck, lip, esophagus, stomach, trachea and lung, breast and other location
4. Undifferentiated carcinoma of gastrointestinal (GI) tract
5. Adenocarcinoma with variants of small intestine
6. Squamous cell carcinoma with variants of GI tract (stomach small intestine, colon, rectum, pancreas)
7. Fibromixoma and low grade mucinous adenocarcinoma (pseudomixoma peritonei) of the appendix and ovary
8. Rare pancreatic tumors including acinar cell carcinoma, mucinous cystadenocarcinoma or serous cystadenocarcinoma
9. Intrahepatic Cholangiocarcinoma
10. Extrahepatic cholangiocarcinoma and bile duct tumors
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
14. Trophoblastic tumor: A) Choriocarcinoma
15. Transitional cell carcinoma other than that of the renal, pelvis, ureter, or bladder
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
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)
21. Odontogenic malignant tumors
22. Endocrine carcinoma of pancreas and digestive tract
23. Neuroendocrine carcinoma including carcinoid of the lung
24. Pheochromocytoma, malignant
25. Paraganglioma
26. Carcinomas of pituitary gland, thyroid gland parathyroid gland and adrenal cortex
27. Desmoid tumors
28. Peripheral nerve sheath tumors and NF1-related tumors
29. Malignant giant cell tumors
30. Chordoma
31. Adrenal cortical tumors
32. Tumor of unknown primary (Cancer of Unknown Primary; CuP)
33. Not Otherwise Categorized (NOC) Rare Tumors [To obtain permission to enroll in the NOC cohort, contact: S1609SC@swog.org]
34. Adenoid cystic carcinoma
35. Vulvar cancer
36. MetaPLASTIC carcinoma (of the breast)
37. Gastrointestinal stromal tumor (GIST)

Condition or disease	Intervention/treatment	Phase
Acinar Cell Carcinoma; Adenoid Cystic Carcinoma; Adrenal Cortex Carcinoma; Adrenal Gland Pheochromocytoma; Anal Canal Neuroendocrine Carcinoma; Anal Canal Undifferentiated Carcinoma; Appendix Mucinous Adenocarcinoma; Bartholin Gland Transitional Cell Carcinoma; Bladder Adenocarcinoma; Cervical 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; Fallopian Tube Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Fibromyxoid Tumor; Gastric Neuroendocrine Carcinoma; Gastric Squamous Cell Carcinoma; Gastric Undifferentiated Carcinoma; Gastrointestinal Stromal 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 Testicular Sex Cord-Stromal Tumor; Metaplastic Breast Carcinoma; Metastatic Malignant Neoplasm of Unknown Primary Origin; 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; Pituitary Gland Carcinoma; Placental Choriocarcinoma; Placental-Site Gestational Trophoblastic Tumor; 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 Malignant Transformation; 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	Procedure: Biospecimen Collection; Biological: Ipilimumab; Biological: Nivolumab	Phase 2

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.

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 ORR (irORR), and immune-related PFS (irPFS) by unidimensional immune-related response criteria.

TERTIARY OBJECTIVES:

I. To evaluate the association of tumor mutational burden measured by tissue sequencing with durable response (complete response [CR] or partial response [PR] lasting 24 weeks or more).

II. To describe the mutational load and targeted sequencing of well-known oncogenes and changes in these markers of patients at up to three time points (baseline, cycle 2, and progression), and across strata to describe associations with survival outcomes.

III. To describe the presence of germline mutations, and across strata to evaluate association with outcome.

IV. Within strata, to describe patient risk category as defined by the biodesix protein signature and change over time at up to three time points (baseline, cycle 2, progression), and across strata to evaluate associations with outcomes.

V. Within strata, to evaluate the association of PD-L1 expression (positive versus negative) with response and survival outcomes, and within strata, to characterize baseline PD-L1 prevalence.

VI. To collect specimens for banking for use in future correlative biomarker research studies.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on day 1. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.

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

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	707 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors
Actual Study Start Date :	January 13, 2017
Estimated Primary Completion Date :	August 31, 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Treatment (nivolumab, ipilimumab); Patients receive nivolumab IV over 30 minutes on days 1, 15, and 29 and ipilimumab IV over 60 minutes on day 1. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.	Procedure: Biospecimen Collection; Undergo optional collection of biopsy tissue and blood; Biological: Ipilimumab; Given IV; Other Names: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo

Outcome Measures

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Primary Outcome Measures :

1. Overall response rate (ORR) defined as confirmed and unconfirmed complete and partial response [ Time Frame: Up to 10 years ]
   Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patients are eligible under ONE of the following criteria:

  • Patients must have histologically confirmed rare cancer and must be able to submit specimens; 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 this study
  • 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 that do not qualify for one of the histologic cohorts 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
• Patients that 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

• 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
• 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; all disease must be assessed and documented on the S1609 Baseline Tumor Assessment Form

• 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
• Patients may have received prior anti-CTLA4 or other anti-PD-1/anti-PD-L1 therapy, not both, provided that it is completed >= 4 weeks prior to registration
• 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 with clinically controlled thyroiditis or pituitary disorders on stable replacement therapy are eligible

• Patients are not eligible if they have had or are planned for solid organ transplant; patients who have received allogeneic hematopoietic stem cell transplant are eligible if:

  • The transplant occurred at least 90 days prior to registration,
  • Patient has no prior acute graft versus host disease (GVHD), and
  • Within 48 hours of registration, patient demonstrates at least 90% engraftment, defined as: absolute neutrophil count (ANC) >= 500 mcl, measured over 3 consecutive days or 1 day with an ANC >= 1,000 mcl, or platelets >= 50,000 mcl measured, wherein the patient did not receive any platelet transfusions within 7 days prior to laboratory assessment
• 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; metastatic brain parenchymal disease must have been treated and patient must be off steroids for 7 days prior to registration; patients must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to registration
• 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 enrollment onto S1609
• Patients must not have prior history of allergy or known hypersensitivity to nivolumab or ipilimumab
• Patients must have a Zubrod performance status of 0-2
• Within 28 days prior to registration: 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
• 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; Note: TSH, with reflex T4 is allowable if per institutional standard; otherwise, both TSH and free-T4 must be obtained
• Patients must have adequate adrenal axis function, as evidenced by adrenocorticotropic hormone (ACTH) values within the institutional normal ranges OR cortisol levels within institutional normal ranges (ante meridiem [AM] cortisol preferred), within 28 days prior to registration
• Females of childbearing potential must have negative serum or urine pregnancy test 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; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive 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, he/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 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, or in the opinion of the treating investigator is well-controlled, are eligible

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

  1. Cluster of differentiation (CD)4+ cell count greater or equal to 250 cells/mm^3
  2. If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment; once daily combinations that use pharmacologic boosters may not be used
  3. No history of non-malignancy acquired immunodeficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts
• 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 doses higher than prednisone 10mg or equivalent); 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 Chron'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]); 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 have amylase or lipase within =< 1.5 x IULN without symptoms of pancreatitis at registration, within 28 days prior to registration
• Patients must not have symptomatic interstitial lung disease or pneumonitis
• Patients must have fully recovered from any adverse effects of major surgery (to =< grade 1) at least 14 days prior to registration

Contacts and Locations

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  Show 854 Study Locations

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Sandip Patel	Southwest Oncology Group

More Information

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT02834013 History of Changes
Other Study ID Numbers:	NCI-2016-01041; NCI-2016-01041 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); S1609; S1609 ( Other Identifier: SWOG ); S1609 ( Other Identifier: CTEP ); U10CA180888 ( U.S. NIH Grant/Contract )
First Posted:	July 15, 2016
Last Update Posted:	September 20, 2018
Last Verified:	August 2018

Additional relevant MeSH terms:

Carcinoma; Neoplasms; Carcinoma, Squamous Cell; Adenocarcinoma; Neoplasms, Germ Cell and Embryonal; Breast Neoplasms; Nasopharyngeal Neoplasms; Cholangiocarcinoma; Gastrointestinal Stromal Tumors; Germinoma; Ovarian Neoplasms; Carcinoma, Transitional Cell; Carcinoma, Adenoid Cystic; Teratoma; Carcinoid Tumor	Seminoma; Choriocarcinoma; Pheochromocytoma; Carcinoma, Neuroendocrine; Cystadenocarcinoma; Carcinoma, Endometrioid; Chordoma; Cystadenocarcinoma, Serous; Paraganglioma; Carotid Body Tumor; Trophoblastic Neoplasms; Gestational Trophoblastic Disease; Neoplasms, Second Primary; Adenocarcinoma, Mucinous; Nerve Sheath Neoplasms