Table 2.
Clinical Trials for NF1 Plexiform Neurofibromas
| Phase 1 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Enrollment Dates | Agent (Route) | Mechanism of Action | Trial Design | Median Age (Range) (Years) | N | Median Baseline PN Volume (Range) (ml) | MTD | DLT | Response Data | Reference |
| 1997–1999 | Thalidomide (po) | Inhibit angiogenesis, anti-inflammatory (TFN-alpha) | 4 cohorts of 5 patients; dose-escalation | 17.5 (6–41)a | 20 | NA | 4 mg/kg/d (max 200 mg/d) continuous | None | 4 with minor response (2D) | 104 |
| 1998–2000 | Tipifarnib (po) |
Farnesyl transferase inhibitor | 3 + 3 | 6 (4–16) | 42 (17 w/NF1) | NA | 200 mg/m2/dose BID for 21 of 28 day cycle | Myelosuppression, rash, GI toxicity | NA (2D) |
105 |
| 2001–2006 | Peginterferon alpha-2b (sc) |
Inhibit proliferation and angiogenesis | 3 + 3 | 9.3 (1.9–34.7) | 30 | NA | 1 μg/kg/wk | Fatigue, behavior changes, neutropenia, myoclonus, ↑ AST/ALT | 1/17 pts (3D) | 106 |
| 2003 | Pirfenidone (po) |
Antibiotic- modulates cytokine action Anti fibrotic |
Pharmacokinetically-guided dose-escalation | 10.5 (3–19) | 16 | NA | 500 mg/ m2/dose TID continuous | Diarrhea, nausea and vomiting | No PR (3D) |
107 |
| 2008 | Photodynamic Therapy (iv, implantable light source) |
LS11 photosensitizer + light leads to vascular occlusion, thrombosis | 3 + 3 | NA | NA | NA | NA (study halted early due to equipment unavailability) | NA | NA | NCT 00716469 |
| 2008–2011 | Sorafenib (po) |
Inhibitor of CRAF, BRAF, RTK (VEGFR-2,3, PDGFR-β, c-kit, Flt3) | 3 + 3 | 8 (6–12) | 9 | 443 (5–10,162) | Unable to determine; intolerable | Tumor pain, rash, mood alteration | No PR (3D) |
108 |
| 2011–2014 | Selumetinib (po) |
MEK inhibitor | 3 + 3 | 10.9 (3–18.5) | 24 | 1205 (29–8,744) | 25 mg/ m2/dose BID continuous dosing | Elevated CPK, cellulitis, urticaria, decreased LVEF, mucositis, rash | PR 17/24 (3D) |
86 |
| 2015–2017 | Pexidartinib (PLX3397) (po) |
Microenvironment | Rolling six, 3 dose levels | 16 (4–21) | 16 (3 w/NF1) | NA | No MTD, highest dose level tolerated: 800 mg/m2/dose continuous dosing | None | No PR for NF1 patients | 109 |
| Phase 2 | ||||||||||
| Dates |
Agent
(Route) |
Target
(Tumor Cell, Microenvironment, Both) |
Trial Design | Median Age (Range) (Years) | N | Median Baseline PN Volume (Range) (ml) | Median TTP (mo)/N with PR (PN Volume ≥ 20%↓) | Max PN Volume Decrease | Activity (Yes/No) | Reference |
| 2001–2007 | Placebo | Placebo | Randomized, placebo controlled, double blinded, cross-over (TTP) | 8.5 (3–21.5) | 29 | 316 (39.6–4896) | TTP = 10.6 mo/0 PR | 7% | NA | 76 |
| Tipifarnib | Tumor | 31 | 572 (20.5–5573) | TTP = 19.2 mo/0 PR | 11% | No | ||||
| 2000–2004 | Pirfenidone- Adults (po) |
Microenvironment | Open label, single arm, | 30 (±13.5)a | 24 | NA | NA | >30% | 7/24 PR (≥15% PN decrease 3D) | 110 |
| 2004–2010 | Pirfenidone- Children and young adults (po) |
Microenvironment | Open label, single arm | 8.9 (3–18.8) | 36 | 349 (15–5629) | TTP = 13.2 mo/0 PR | 12% | No | 84 |
| 2006–2009 | Imatinib (po) |
Both | Open label, single arm | 13 (3–52) | 36 | NA | 6 PR | 38% | Yes | 111 |
| 2006–2014 | Peginterferon alpha-2b (sc) |
Both | Stratum 1: Asymptomatic PN | 12.4 (2.8–20.5) | 27 | 440 (9.4–6370) | 1 PR (not confirmed) |
NA | No | 85 |
| Stratum 2: Orbital PN, PN with pain, or PN with decrease in performance status | 9.4 (1.7–21.1) | 26 | Orbital PN 178 (34–283) Pain PN 503 |
|||||||
| (95–13,327) Performance status PN 615 (9.7–1,018) |
1 PR | NA | No | |||||||
| Stratum 3: Progressive PN | 7.1 (1.6–17.6) | 29 | 288 (14–3102) | TTP = 29.4 mo | NA | Yes | ||||
| 2008–2014 | Sirolimus (po) |
Tumor | Stratum 1: Progressive PN | 7.9 (3–45.4) | 49 | 186 (13–4808) | TTP = 15.4 mo 0 PR |
17% | Yes | 112 |
| Stratum 2: Nonprogressive PN | 16 (3–35) | 12 | 784 (23–2476) | 0 PR | 7.4% | No | 113 | |||
| 2011–2014 | Everolimus (RAD001) (po) |
Tumor | Open label, single arm | 31.6 (19.5–46.4)a | 23 | 54.5 (9–453.8) | 0 PR | NA | No | 114 |
| 2014–2017 | Mirdametinib (PD-0325901) (po) |
Tumor | Open label, single arm | 24 (16–39) | 19 | 797.8 (NA) | 8 PR | 28% | NA | 63 |
| Phase 2 | ||||||||||
| Dates |
Agent
(Route) |
Target
(Tumor Cell, Microenvironment, Both) |
Trial Design | Median Age (Range) (Years) | N | Median Baseline PN Volume (Range) (ml) | Median TTP (mo)/N with PR (PN Volume ≥ 20%↓) | Max PN Volume Decrease | Activity (Yes/No) | Reference |
| 2014-present | Cabozantinib (XL184) (po) |
Both | Stratum 1: Adults | 22 (16–34) | 23 | 557 (57–2954) | 8 PR (of 19 evaluable) | 38% | Yes | 64 |
| Stratum 2: Pediatric | NA | NA | NA | NA | NA | NA | NCT 02101736 | |||
| 2015–present | Selumetinib (po) |
Tumor | Stratum 1: PN morbidity | 10.2 (3.5–17.4) | 50 | 487 (5–3820) | 37 PR | 55.1% | Yes | 54 |
| Stratum 2: No PN morbidity | 12.3 (4.5–18.1) | 25 | 381(12–3159) | 18 PR | 46.3% | Yes |
115
NCT 01362803 |
|||
| 2015–present | Trametinib (po) |
Tumor | Phase 1/2 dose escalation, disease expansion | 5.5 (1–16) | 26 | NA | 12 PR | NA | Yes |
90
NCT 02124772 |
| 2016–present | Selumetinib (po) |
Tumor | Open label, single arm (adults) | 33 (18–60) | 23 | NA | 16 PR | 41% | Yes |
87
NCT 02407405 |
| 2017–present | Binimetinib (MEK162) (po) |
Tumor | Stratum 1: Adults | 23 (18–55) | 25 | 410 (7–3129) | 13 PR (of 20 evaluable) | 35.2% | Yes |
88,89
NCT 03231306 |
| Stratum 2: Pediatric | 12 (2–16) | 20 | 326 (8–6661) | 14 PR | 54% | Yes | ||||
| 2019–present | Mirdametinib (PD-0325901) (po) |
Tumor | Stratum 1: Adults | NA | NA | NA | NA | NA | NA | NCT 03962543 |
| Stratum 2: Pediatric | ||||||||||
Abbreviations: CPK, creatine phosphokinase; D, day; DLT, dose limiting toxicity; ED, erectile dysfunction; GI, gastrointestinal; iv, intravenous; LVEF, left ventricular ejection fraction; mo, months; MTD, maximum tolerated dose; N, number; NA, not available; PN, plexiform neurofibroma; po, oral; PR, partial response; sc, subcutaneous; TNF, tumor necrosis factor; TTP, time to progression; 2D, area; 3D, volumetric.
aMean age reported.