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
- 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.
- 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 5.1.3.4. 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.
