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Rapid Analysis and Response Evaluation of Combination Anti-Neoplastic Agents in Rare Tumors (RARE CANCER) Trial: RARE 1 Nilotinib and Paclitaxel

Trial Status: Active

Background: People with rare cancers often have limited treatment options. The biology of rare cancers is not well understood. Researchers want to find better treatments for these cancers. They want to test 2 drugs that, taken separately, have helped people with non-rare cancers. They want to see if these drugs together can make rare cancers shrink or stop growing. Objective: To learn if nilotinib and paclitaxel will benefit people with rare cancers. Eligibility: People age 18 and older who have a rare, advanced cancer that has progressed after receiving standard treatment, or for which no effective therapy exists. Design: Participants will be screened with medical history and physical exam. They will have blood and urine tests. They will have a pregnancy test if needed. They will have an electrocardiogram to check their heart. They will have imaging scans to measure their tumors. Participants will repeat the screening tests during the study. Participants will receive nilotinib and paclitaxel. The drugs are given in 28-day cycles. Nilotinib is a capsule taken by mouth twice a day. Paclitaxel will be given intravenously by peripheral line or central line once a week for the first 3 weeks of each cycle. Participants will keep a medicine diary. They will track when they take the study drugs and any side effects they may have. Participants may have optional tumor biopsies. Participants can stay on the study until their disease gets worse or they have intolerable side effects. Participants will have a follow-up phone call about 30 days after taking the last dose of study drugs.

Inclusion Criteria

  • - INCLUSION CRITERIA: - Patients must have histologically confirmed rare solid tumors that have progressed on standard therapy known to prolong survival or for which no standard treatment options exist. The list of eligible rare tumors can be found below**; other rare tumor types may be acceptable at the discretion of the PI. - Patients must have measurable and evaluable disease. - Age >= 18 years. - ECOG performance status <= 2. - Patients must have normal organ and marrow function as defined below: - Absolute neutrophil count >=1,500/mcL - Platelets >=100,000/mcL - Total bilirubin <=1.5 X institutional ULN - AST(SGOT)/ALT(SGPT) <=3 X institutional upper limit of normal; <= 5.0 x ULN in patients with liver metastases - creatinine <=1.5 X institutional ULN OR - creatinine clearance >=60 mL/min/1.73 m^2 for patients with creatinine levels >1.5 mg/dL - Nilotinib and paclitaxel have both been assigned to pregnancy category D by the FDA. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for at least 3 months after dosing with study drugs ceases. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of study drug administration. - Patients must have completed radiation therapy or major surgery >= 3 weeks, or biologic therapy or chemotherapy >= 5 half-lives or 3 weeks, whichever is shorter (6 weeks for nitrosoureas and mitomycin C) prior to entering the study. Patients must be >= 2 weeks since any prior administration of a study drug in a Phase 0 or equivalent study and be >= 1 week from palliative radiation therapy (patients on study may be eligible for palliative radiotherapy to non-targeted lesions after 2 cycles of therapy at the PI s discretion). Patients must have recovered to eligibility levels from prior toxicity or adverse events. Treatment with bisphosphonates is permitted. - Biopsies are optional on this study. In lieu of baseline biopsies, patients are encouraged to submit at registration archival tumor biopsy tissue from a previous research study or medical care providing it meets the minimum collection and preservations requirements outlined in Section Criteria for the submission of archival tissue are: - Tissue must have been collected within 3 months prior to registration. - Patient must not have received any intervening therapy for their cancer since the collection of the tumor sample. - Rare Tumor Eligibility List 1. Epithelial tumors of nasal cavity, sinuses, 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 (a.k.a. adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma, or invasive mucinous adenocarcinoma) 13. Non-epithelial tumors of the ovary 14. Trophoblastic tumor 15. Transitional cell carcinoma other than that of the renal, pelvis, ureter, or bladder 16. Cell tumor of the testes and extragonadal germ tumors 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. Pancreatic neuroendocrine tumor (PNET) 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 34. Adenoid cystic carcinoma 35. Vulvar cancer 36. MetaPLASTIC carcinoma (of the breast) 37. Gastrointestinal stromal tumor (GIST) 38. Perivascular epithelioid cell tumor (PEComa) 39. Apocrine tumors/Extramammary Paget s Disease 40. Peritoneal mesothelioma 41. Basal cell carcinoma 42. Clear cell cervical cancer 43. Esthenioneuroblastoma 44. Endometrial carcinosarcoma (malignant mixed Mullerian tumors) 45. Clear cell endometrial cancer 46. Clear cell ovarian cancer 47. Gestational trophoblastic disease (GTD) 48. Gallbladder cancer 49. Small cell carcinoma of the ovary, hypercalcemic type 50. Angiosarcoma 51. High-grade neuroendocrine carcinoma 52. Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) 53. Anal cancer 54. Lymphoma 55. Merkel cell carcinoma 56. Pleural Mesothelioma 57. Sarcoma (bone & soft tissue) 58. Thymic Carcinoma 59. Uterine Leiomyosarcoma 60. Papillary RCC EXCLUSION CRITERIA: - QTcF interval of >=450 msec at study entry; congenital long QT syndrome - Sensory/motor neuropathy >= Grade 2 - Patients who are receiving any other investigational agents. - Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions: - Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met: - Evaluable or measurable disease outside the CNS - No metastases to brain stem, midbrain, pons, medulla, or cerebellum - No history of intracranial hemorrhage or spinal cord hemorrhage - No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted. - No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, Day 1 - Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following: - Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and radiographic screening for the current study - No stereotactic radiation or whole-brain radiation within 28 days prior to Cycle 1, Day 1 - Screening CNS radiographic study >=4 weeks from completion of radiotherapy and >=2 weeks from discontinuation of corticosteroids - History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs. - Uncontrolled intercurrent illness including, but not limited to, serious untreated infection, symptomatic respiratory failure/congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. - Pregnant women are excluded from this study because nilotinib and paclitaxel have been assigned to pregnancy category D by the FDA. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 3 months following the last dose of study drug. - Patients who are known to be HIV-positive and on combination antiretroviral therapy are ineligible because of possible PK interactions with study drugs.


National Institutes of Health Clinical Center
Status: ACTIVE
Contact: NCI Clinical Trials Referral Office
Phone: 888-624-1937


- Rare tumors constitute a heterogeneous group of cancers associated with limited

treatment options and poor outcomes. Due to their rarity, there are few good models for

these diseases to support preclinical evaluation of new anticancer agents. To address

these challenges, DCTD s Patient-Derived Models Repository (PDMR) is generating

patient-derived xenograft models of adult and pediatric rare cancers and has screened

combinations of approved and investigational anticancer agents in these models.

- Based on preclinical activity, drug combinations are being tested in patients with rare

cancers in a series of connected Phase 2 clinical trials (Rapid Analysis and Response

Evaluation of Combination Anti-Neoplastic Agents in Rare Tumors [RARE CANCER]);

responses may trigger further evaluation of a treatment in that rare cancer type to

further evaluate response rate and mechanism-of-action. Patients who progress will be

offered another RARE CANCER trial.

- The agents used in this trial are the BCR-Abl kinase inhibitor nilotinib and the

anti-tubulin agent paclitaxel, which showed greater than additive activity in

combination in preclinical xenograft models and subsequently demonstrated clinical

efficacy (including partial responses) in patients with solid tumors on the Phase 1

trial 15-C-0086 (NCT02379416).

Primary Objectives:

- To evaluate the proportion of patients with advanced rare cancers who have objective

responses (OR) to treatment with nilotinib and paclitaxel

Exploratory Objectives:

- To evaluate the proportion of patients alive and progression free at 6 months on study


- To identify genomic and transcriptomic determinants of response and resistance in tumor

biopsy specimens

- To examine genomic alterations in circulating tumor DNA (ctDNA) and circulating tumor

cells (CTCs) that may be associated with response or resistance

- To evaluate the pharmacodynamic effects of the combination on biomarkers of cell death

and epithelial-to-mesenchymal transition in tumor tissue and CTCs


- Study participants must have a histologically confirmed solid tumor meeting the RARECARE

definition of rare tumor that has progressed on standard therapy known to prolong

survival or for which no standard treatment options exist

- Age >= 18

- No major surgery, radiation, or chemotherapy within 3 weeks prior to entering the study

(6 weeks for nitrosoureas and mitomycin C) or 5 half-lives of the agent, whichever is

shorter; toxicity from prior treatment must have recovered to eligibility levels.

- Adequate organ function; performance status ECOG 0-2

Study Design:

- Nilotinib will be administered at 300 mg orally BID and paclitaxel will be administered

IV at 80 mg/m2 on Days 1, 8, and 15 in 28-day cycles.

- A single-stage design will be used with a target accrual of 30 eligible patients. If at

least 4/30 patients experience an objective response (PR or CR by RECIST 1.1), the

combination of nilotinib and paclitaxel will be considered promising. The accrual

ceiling is 34 patients.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
National Cancer Institute

Principal Investigator
Naoko Takebe

  • Primary ID 200121
  • Secondary IDs NCI-2020-04956, 20-C-0121
  • ID NCT04449549