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

Background:

• 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 agents
• 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

Eligibility:

• 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; with Mod G (6-17-24), eligibility will be limited to patients with granulosa cell ovarian cancer, clear cell ovarian cancer, anal cancer, or Ewing sarcoma.
• 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/m^2 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.

• 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**. With Amendment G (v 6-17-24), eligibility will be limited to patients with adult granulosa cell ovarian cancer, clear cell ovarian cancer, anal cancer, or Ewing sarcoma.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 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.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. For these patients, an HIV viral load test must be completed within 28 days prior to enrollment.

• Rare Tumor Eligibility List

• Epithelial tumors of nasal cavity, sinuses, nasopharynx
• Epithelial tumors of major salivary glands
• Salivary gland type tumors of head and neck, lip, esophagus, stomach, trachea and lung, breast and other location
• Undifferentiated carcinoma of gastrointestinal (GI) tract
• Adenocarcinoma with variants of small intestine
• Squamous cell carcinoma with variants of GI tract (stomach small intestine, colon, rectum, pancreas)
• Fibromixoma and low-grade mucinous adenocarcinoma (pseudomixoma peritonei) of the appendix and ovary
• Rare Pancreatic tumors including acinar cell carcinoma, mucinous cystadenocarcinoma or serous cystadenocarcinoma
• Intrahepatic cholangiocarcinoma
• Extrahepatic cholangiocarcinoma and bile duct tumors
• Sarcomatoid carcinoma of lung
• Bronchoalveolar carcinoma lung (a.k.a. adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma, or invasive mucinous adenocarcinoma)
• Non-epithelial tumors of the ovary
• Trophoblastic tumor
• Transitional cell carcinoma other than that of the renal, pelvis, ureter, or bladder
• Cell tumor of the testes and extragonadal germ tumors
• Epithelial tumors of penis - squamous adenocarcinoma cell carcinoma with variants of penis
• Squamous cell carcinoma variants of the genitourinary (GU) system
• Spindle cell carcinoma of kidney, pelvis, ureter
• Adenocarcinoma with variants of GU system (excluding prostate cancer)
• Odontogenic malignant tumors
• Pancreatic neuroendocrine tumor (PNET)
• Neuroendocrine carcinoma including carcinoid of the lung
• Pheochromocytoma, malignant
• Paraganglioma
• Carcinomas of pituitary gland, thyroid gland parathyroid gland and adrenal cortex
• Desmoid tumors
• Peripheral nerve sheath tumors and NF1-related tumors
• Malignant giant cell tumors
• Chordoma
• Adrenal cortical tumors
• Tumor of unknown primary (Cancer of Unknown Primary; CuP)
• Not Otherwise Categorized (NOC) Rare Tumors
• Adenoid cystic carcinoma
• Vulvar cancer
• MetaPLASTIC carcinoma (of the breast)
• Gastrointestinal stromal tumor (GIST)
• Perivascular epithelioid cell tumor (PEComa)
• Apocrine tumors/Extramammary Paget s Disease
• Peritoneal mesothelioma
• Basal cell carcinoma
• Clear cell cervical cancer
• Esthenioneuroblastoma
• Endometrial carcinosarcoma (malignant mixed Mullerian tumors)
• Clear cell endometrial cancer
• Clear cell ovarian cancer
• Gestational trophoblastic disease (GTD)
• Gallbladder cancer
• Small cell carcinoma of the ovary, hypercalcemic type
• Angiosarcoma
• High-grade neuroendocrine carcinoma
• Treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC)
• Anal cancer
• Lymphoma
• Merkel cell carcinoma
• Pleural Mesothelioma
• Sarcoma (bone & soft tissue)
• Thymic Carcinoma
• Uterine Leiomyosarcoma
• 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.