Table 1.
Clinical trials of 9-aminocamptothecin (9-AC) and 9-nitrocamptothecin (9-NC, rubitecan)
| Key | Route & dose | Formulation | Cancer type and key clinical trial outcome | Refs |
|---|---|---|---|---|
| 1995 9-AC Phase I | 72 h iv 3 wk/c*; MTD: 45 µg/m2/h | Dissolve in DMA, PEG400, phosphoric acid (see No 2) | 31 pts w resistant solid tumors; DLT: NP, TCP; minimal responses were seen in pts w gastric, colon, and NSCLC; try alternative schedules. | No 1 [123] |
| 1996 9-AC Phase I | 72 h iv at 0.1 mg/ml; 2 wk/c*; | 2% DMA, 98% PEG400 w 10 mM phosphoric acid diluted w saline | 48 pts w progressive solid tumor, DLT: NP; PR: 1 pt (finally progressed); 1 pt w 49% shrinkage in pulmonary nodules; 1 NSCLC pt w a 29% decrease in his lung metastases. MTD: 35 µg/m2/h or 47 µg/m2/h w G-CSF | No 2 [124] |
| 1996 9-NC Phase I | po: CPT at 0.3 mg/m2/d x 21 4 wk/c,; 9-NC at 1 mg/m2/d, 5/wk* | Drug powder is encapsulated in gelatin capsules (see No 7 and No 34) | 52 (CPT) and 29 (9-NC) pts w refractory solid & liquid cancer; DLT: CPT, diarrhea; 9-NC, NP, anemia and TCP; favorable responses (11% CPT, 24% 9-NC). | No 3 [125] |
| 1997 9-AC Phase I | 72 h iv 2 wk/c*; 5-74 µg/m2/h | Same as No 5 (also see No 2) | 48 pts w malignant solid tumor; total 9-AC circulating in plasma as the active lactone was less than 10%, no antitumor activity reported. | No 4 [126] |
| 1997 9-AC Phase II | 72 h iv at 35 µg/m2/h in 2 wk, 4 wk/c* | 0.1 mg/ml in 2% DMA, 49% PEG400 w 5 mM phosphoric acid (see No 2) | 17 naïve pts w metastatic colorectal carcinoma; No CR or PR; toxicity: neutropenia, nausea, vomiting, stomatitis, fatigue, and anemia but tolerated; lack of antitumor activity | No 5 [127] |
| 1997 9-AC Phase II | 72 h iv at 59 then 50 µg/m2/h w G-CSF in 2 wks* | Same as No 5 (also see No 2) | 16 pts w metastatic colorectal cancer; no OR; SD: 8 pts; DLT: myelosuppression; conclusion: no promising for this regimen | No 6 [128] |
| 1998 9-AC Phase I | po, 1.5 on d1 & iv, 1 mg/m2 on d8 or vice versa | Gelatin capsule containing 9-AC-PEG1000 molten mix | 12 pts w solid tumors; active lactone accounting for < 10% of total drug at the terminal disposition phase; the study is not activity focused | No 7 [129] |
| 1998 9-AC Phase I | 72 h iv at ≥ 37.5 µg/m2/h, 3 wk/c*; | Lyophilized CD in DMPC, DMPG & mannitol in 20% dextrose/saline | 25 pts w primary solid tumors; DLT: NP; OR: 0 pt; SD: 9 pts for 2-6 months; Phase II: 54.2 µg/m2/h, 72 h iv infusion every 3 weeks. | No 8 [130] |
| 1998 9-AC Phase I | 72 h iv at 36 to 62 µg/m2/h, 3 wk/c* | DMA-PEG400-phosphoric acid (see No 2). | 23 pts w resistant solid tumors; DLT: NP, TCP; PR: 2 pts; SD: 5 pts; Phase II: 52 µg/m2/h, 72 h iv infusion every 3 weeks (21 days). | No 9 [131] |
| 1998 9-AC Phase I | po, d1-5 at 0.2-0.68 mg/m2/d in 2 wk*; | CD formulation (see No 8) | 16 cancer pts; DLT: nausea; OR: 0 pt; conclusion: the CD formulation for iv is not good for po | No 10 [132] |
| 1998 9-AC Phase II | 120 h iv/wk x 3 wks* at 480 µg/m2/d | Not clear, likely used the No 2 recipe | 17 naïve pts w metastatic colorectal cancer; no responses observed; toxicity: granulocytopenia, nausea, vomiting and diarrhea | No 11 [133] |
| 1998 9-AC Phase I | 24 h iv/wk x4 at 0.7-1.9 mg/m2, 5 wk/c* | CD formulation (see No 8) | 16 of 20 pts w 5-Fu resistant colorectal cancer; toxicity: NP and diarrhea; Phase II: 1.65 mg/m2 | No 12 [134] |
| 1998 9-NC Phase I | Po d1-5/wk at 1, 1.5, 2 mg/m2/d in turn for 28, 68 & 159 wks | Not clear (full paper is inaccessible) | 43 pts w resistant metastatic cancer; DLT: anemia, NP, TCP, diarrhea; 5 pts w pancreatic, breast, ovarian & hematologic tumors had response; DS: 14 pts; 1 pt got 18-month TX | No 13 [135] |
| 1998 9-AC Phase II | 72 h iv in 2 wk*; at 59-45.8 µg/m2/h w G-CSF | DMA-PEG400-phosphoric acid (see No 2). | 58 pts w IIIB/IV NSCLC; PR: 5 pts; toxicity: NP, TCP; data not suggested further evaluation w the doses and schedule used. | No 14 [136] |
| 1998 9-AC Phase II | 72 h iv in 3 wk* at 40 µg/m2/h | DMA-PEG400-phosphoric acid (see No 2). | 45 pts w relapsed or refractory lymphomas; PR: 10 pts; G-CSF reduced NP & diarrhea rates, but no help in dose increase; DLT: TCP. | No 15 [137] |
| 1999 9-AC Phase I | po d1-7 or d1-14 at 0.25 to 1.1 mg/m2/d 3 wk/c*; | Gelatin capsules: same as or similar to No 7 | 30 pts w solid tumors; DLT: NP, TCP; PR: 1 pt; (recommended) phase II dose: 0.84 mg/m2/d | No 16 [138] |
| 1999 9-AC Phase I | po at 0.25 to 1.5 mg/m2/d on d1, d6 or on d1, d8; | Gelatin capsules: same as or similar to No 7 | 32 pts w solid tumors; PK focus; linear and dose-independent PK w small intrapatient kinetic variability; lactone form > 10% | No 17 [139] |
| 1999 9-AC Phase I | 0.5 h iv at ≥ 0.4 mg/m(2)/d on d1-5/wk x 3 | CD (see No 8); further dilution w saline if needed | 31 pts w resistant solid tumors; DLT: TCP, NP; PR: 1 pt; recommend phase II: 1.1 mg/m2/d; there is 10% lactone form | No 18 [140] |
| 1999 9-AC Phase II | 72 h iv at 35.4-59 µg/m2/h in 2 wk x 2; | DMA-PEG400-phosphoric acid (see No 2). | 80 pts w solid tumors; NP was the main toxicity; no tumor response; no lactone versus carboxylate information but a total of both were measured. | No 19 [141] |
| 1999 9-NC Phase II | po d1-4/wk* at 1.5 mg/m2/d | Not clear (full paper is inaccessible) | 29 pts w resistant ovarian, tubal or peritoneal cancer; 7% remission and 34% obtained SD. Major toxicity: anemia, NP, TCP and diarrhea. | No 20 [142] |
| 1999 9-AC Phase I | 7 d iv at ≥ 0.2 mg/m2/d in 3-4 wk x ≤ 2*; | CD (see No 8); 100 µg/ml further dilution w sterile water | 39 pts w resistant blood cancer; major toxicity: mucositis and diarrhea; no complete or partial remission was observed. | No 21 [143] |
| 1999 9-NC Phase II | po at 1.5 mg/m2/d d1-5/wk in 8 wk*; | Capsule form (SuperGen provided (see No 7) | 107 pts w advanced pancreatic cancer; 60 pts finished 2 8 wk courses; safe & efficacious; DLT: myelosuppression, interstitial cystitis | No 22 [144] |
| 2000 9-AC Phase II | 72 h iv at 45 µg/m2/h; w G-CSF in 2 wk x ≥ 1*; | Not described in the paper | 18 pts w resistant breast cancer; major toxicity: granulocytopinia and TCP; 2 out of 15 assessable pts showed limited responses. | No 23 [145] |
| 2000 9-AC Phase II | 72 h iv at 35.4 µg/m2/h in 2 wk x ≥ 1*; | Like used the recipe in No 2 | 14 pts w H&N SCC; OR: 0 pt; hematologic toxicity was modest and promptly reversible. | No 24 [146] |
| 2000 9-AC Phase II | 72 h iv or 120 iv at 45.8 or 20 µg/m2/h w or w/o G-CSF, 4 wk/c* | DMA-PEG400-phosphoric acid (see No 2) | 51 naïve pts w metastatic colorectal carcinoma; high toxicity (leukopinia, TCP, NP, diarrhea, hepatotoxicity); 1/40 showed response; 3 pts died from treatment toxicity. | No 25 [147] |
| 2000 9-NC Phase I | Aerosolization d1-5 at 6.7 µg/kg/d in 3 wk x 2-14* | Aerosolized liposomal | 6 pts w tumor metastasis to lung; no side effect higher than grade 2 was observed; plasma 9-NC: 37 to 4.9 ng/ml in 24 h; SD: 2 pts | No 26 [148] |
| 2000 9-NC Phase I | po d1-5 at 1.5 mg/d in 3 wk; Cis 30-60 mg/m2/d x 1 | No formulation information provided in the full paper | 12 pts w unclear cancer type; DLT not reached; 10 pts received ≥ 2 courses; OR: 0 pt; | No 27 [149] |
| 2001 9-AC Phase II | 72 h iv/2 wk x ≥ 2* at 46 µg/m2/h w G-CSF | Formulation is not clear (full paper is inaccessible) | 12 pts w advanced lymphoma; the study was prematurely terminated due to toxicity; 3 pts died due to sepsis after their last 9-AC treatment | No 28 [150] |
| 2001 9-NC Phase II | po d1-5/wk at 1.5-2 mg/m3/d up to 37 wk* | Gelatin capsules (no details in full paper); refer to No 7 | 19 pts w advanced pancreatic cancer; OR: 4/14 pts; subjective responses: 13/14; toxicity terminated treatment in 7 pts | No 29 [151] |
| 2001 9-AC Phase I | 120 h iv/3-4 wk x ≥ 2* at 0.41-0.77 mg/m2/d | Both DMA-PEG400-phosphoric acid and CD, no details (see No 2 & No 8) | 55 pts w solid tumors; OR: 1 pt; minor responses on pts w lung and colon cancer were also observed; DLT: NP, TCP, and diarrhea. | No 30 [152] |
| 2002 9-NC Phase II | po d1-5/wk* at 1.5 mg/m2/d | Formation is not clear (full paper is inaccessible) | 28 pts w metastatic melanoma; SD: 4 pts for 3, 4, 6 and 8 months; diarrhea, moderate hematopoietic toxicity, | No 31 [153] |
| 2002 9-AC Phase I | ip q2d x 6/4 wk x ≥ 1c* at 1.25-13.5 mg/m2 | Formation is not clear (full paper is inaccessible) | 12 pts w peritoneal cancer; DLT: NP; 2 pts had objective evidence of clinical benefit and only one had progressive disease | No 32 [154] |
| 2002 9-NC Phase II | po d1-5/3 wk* at 1.5 mg/m2/d | Formulation was not described in the paper. | 15 eligible pts w advanced glioblastoma multiforme; NP and TCP were common; SD: 5 pts; not support for this disease use | No 33 [155] |
| 2002 9-NC Phase II | po (fast vs. food) d1-5/wk* at 1.5 - 2.0 mg/m2/d | Gelatin capsules w drug-lactose mix inside (see No 7) | 19 pts w naive advanced colorectal cancer; DLT: diarrhea, leucopinia, NP; toxicity well tolerated but no objective response; | No 34 [156] |
| 2002 9-NC Phase I | po d1-5/wk x 2 wk at ≥ 0.75 mg/m2/d; Gem, iv | 9-NC from SuperGen Inc, so likely capsule (see No 7) | 21 pts w advanced malignancies; DLT: NT, TCP; SD: 5/18 evaluable pts; MTD: 9NC 1 mg/m2, Gem 1000 mg/m2 on d1and d8/3 wk | No 35 [157] |
| 2003 9-AC Phase I | 72 h iv/2 wks* at 25-59 µg/m2/h | CD formulation (see No 8) | 20 pts w resistant solid tumors; DLT: granulocytopenia; no antitumor response; (recommended) Phase II dose: 47 µg/m2/h | No 36 [158] |
| 2003 9-NC Phase I | po: d1-5/2 wk; combination w capercitabine | Gelatin capsules w 9-NC and lactose inside. | 21 pts w metastatic solid tumors; DLT: nausea, emesis; SD: 9 pts. | No 37 [159] |
| 2003 9-NC Phase II | po d1-5/wk* at 1.5 mg/m2/d | Gelatin capsules w 9-NC w lactose inside. | 56 pts w GI tumor or STS; well tolerated but inactive in GI; minimal activity in pts w STS. | No 38 [160] |
| 2003 9-AC Phase I | iv followed w po using complex schedules. | CD formulation (see No 8 for details) | 32 pts w advanced solid tumors; DLT: anemia, NP, TCP; SD: 2 pts; lack of activity. | No 39 [161] |
| 2004 9-NC Phase II | po d1-5/wk x 3/c* at 1.5 mg/m2/d | Formulation unclear (full paper is inaccessible). | 20 pts w advanced resistant urothelial tract tumors; acceptable toxicity; PR: 1 pt | No 40 [162] |
| 2004 9-AC Phase II | 72 h iv/2 wk* at 35 µg/m2/h | DMA-PEG400-phosphoric acid (see No 2). | 60 pts w ovarian carcinoma treated; 4 full and 6 partial remissions (none was platinum-resistant); SD: 19 pts; DLT: NP, TCP, anemia | No 41 [163] |
| 2004 9-AC Phase II | 120 h iv/2 wk at 25 µg/m2/h 3 wk/c* | Formulation unclear (full paper is inaccessible). | 15 pts w naïve metastatic gastric cancer; SD: 3 pts lasting 3.4 months; DLT: NP, anemia | No 42 [164] |
| 2004 9-NC Phase I/II | po A: d1-5/wk in 2 wk; B: d1-14 in 4 wk; C: d1-5 in 8 wk | crystalline powder in hard gelatin capsules (see No7 and 34) | Pts w solid tumor: 34 on d1 PK, 11 on d10, d11 PK for A; 9 on d10, d11 PK for B; 4 for phase II on d1; focus PK; big interpatient and intrapatient variation of 9-NC vs. 9-AC | No 43 [165] |
| 2004 9-NC Phase II | po d1-5/wk* at 1.5 mg/m2/d | Formulation unclear (full paper is inaccessible). | 17 pts w resistant metastatic breast cancer; SD: 6 pts; nausea, vomiting, fatigue, diarrhea were common | No 44 [166] |
| 2004 9-NC Phase II | po d1-5/wk x 3* at 1.5 mg/m2/d | Gelatin capsules (see No 7) | 35 pts w SCLC; no objective responses were observed; Toxicity was acceptable (TCP, nausea/vomiting, diarrhea) | No 45 [167] |
| 2004 9-NC Phase I | Aerosolization; 6.7-26.6 µg/kg/d x 5 for 1-6 wk | Liposome using dilauroylphosphatidyl choline (DLPC) | 25 pts w advanced lung cancer; the aerosol route is feasible and safe; 2 pts showed partial remissions; SD: 3 pts | No 46 [168] |
| 2004 9-NC Phase I | po d1-5/wk x 2 in 4 wk or d1-14/4 wk | Unclear in full paper (likely capsule, see No 7 or No34) | 26 pts w advanced solid tumors; DLT: NP, TCP, diarrhea; SD: 3 pts; PR: 1 pt; Phase II: 2.43 and 1.70 mg/m2/d | No 47 [169] |
| 2004 9-NC Phase III | po d1-5/wk x 8 wk* at 1.5 mg/m2/d; | SuperGen involved studies; so likely capsule (see No 7) | Resistant pancreatic cancer: 198 pts (9-NC) vs. 211 pts (best care); no median survival difference but MS and PFS favored to 9-NC pts; Conclusions: The study can achieve tumor growth control with an acceptable risk-benefit ratio for the disease with few treatment options. | No 48 [170] |
| 2005 9-NC Phase III | po d1-5/wk* at 1.5 mg/m2; 5-Fu iv weekly at 600 mg/m2 | Capsules | 224 pts w resistant pancreatic cancer; In the evaluable group, 14 of 35 pts achieved tumor growth control (OR: 4 pts; SD: 10 Pts); no survival improvement evidenced; | No 49 [171] |
| No 50 [121] | ||||
| 2005 9-NC Phase II | po d1-5/wk* at 1.25 mg/m2/d | 9-NC from SuperGen Inc, so likely capsule (see No 7) | 51 pts w advanced chordoma, STS or GIST; OR: 2 pts; major toxicity: anemia, leukopenia, fatigue, nausea, diarrhea | No 51 [172] |
| 2005 9-AC Phase II | 120 h iv/wk in 3 wk* at 25 µg/m2/h | CD formulation (see No 8) | 56 pts w platinum-resistant ovarian cancer; major toxicity: NP, leukopenia, anemia, TCP; CR: 4 pts; PR: 4 pts; SD: 18 pts | No 52 [173] |
| 2005 9-NC Phase I | po d1-5/wk• at 1-1.25 mg/m2/d; 45 Gy/5 wks of radiation | 9-NC from SuperGen Inc, so likely capsule (see No 7) | 8 pts w locally advanced pancreatic cancer; DLT: nausea/vomiting, fatigue, anorexia, leukopenia, dehydration; Conclusion: 1 mg/m2/day can be given w radiation | No 53 [174] |
| 2005 9-NC Phase II | po d1-5/wk* at 1.5, 1.75 and/or 2.0 mg/m2/d | Unclear, likely capsule (see No 7) | 17 pts w IIIB(9), IV(8) naive NSCLC; well tolerated (no NP, TCP); SD: 10 pts; conclusion: inactive at doses used for this type of NSCLC. | No 54 [175] |
| 2005 9-NC Phase II | po d1-5/wk x 8 wk at 1.5 mg/m2/d | Unclear, likely capsule (see No 7) | 58 pts w resistant pancreatic cancer; PR: 3/43 pts; SD: 7/43 pts; common toxicity: gastrointestinal and hematologic toxicity | No 55 [176] |
| 2006 9-AC Phase I | 72 h iv/2 wk* at 46 µg/m2/h | Formulation unclear (full paper is inaccessible). | 14 pts w glioblastoma multiforme (GBM); DLT: lymphopenia, NP; lack activity against GBM, no further trial necessary for 9-AC in GBM | No 56 [177] |
| 2006 9-AC Phase I | 7 d (DMA) iv or 21 d (CD) iv at ≥ 6.2 µg/m2/h | Both DMA & CD formulations used (see No 2 and No 8) | 57 pts w resistant solid tumor; DLT: NP, TCP; OR: 6/57 pts; 9AC/CD has ~2x lactone form of those from 9AC/DMA for the same dose level. | No 57 [178] |
| 2006 9-NC Phase I | po d1-3 (9NC at 0.75-2 mg/m2), then etoposide | Formulation not provided in the paper | 45 pts with advanced cancer; DLT: NP, TCP, nausea, vomiting, diarrhea and fatigue in 6 pts; OR: 2 pts; SD: 13 pts; | No 58 [179] |
| 2006 9-NC Phase I | po w or w/o fast at 1.5 mg/m2; then d1-5/wk | 0.5 mg tablets from SuperGen, Inc. (Dublin, CA, USA) | 16 pts w solid tumors; SD: 2 pts for 8 wks; food recued 9-NC absorption but no 9-AC exposure difference; high inter-patient variability | No 59 [180] |
| 2006 9-NC Phase II | po d1-5/wk* at 1.5 mg/m2/d; | Drug from SuperGen Inc, likely capsule (see No 7) | 16 pts w resistant metastatic breast cancer; SD: 5/13 pts; grade 3/4 toxicity: allergy, pain, diarrhea, TCP(2), myalgia | No 60 [181] |
| 2006 9-NC Phase II | po d1-5/wk* at 1.5 mg/m2/d | Formulation unclear (full paper is inaccessible). | 14 pts w advanced 5Fu-resistant colorectal cancer; well tolerated; DLT: anemia, diarrhea; no response/no seen clinical activity. | No 61 [182] |
| 2008 9-NC Phase I | iv Cis on d1, then po 9NC d1-5/wk x 3 wk | Formulation unclear (full paper is inaccessible) | 51 pts w resistant solid tumors; DLT: TCP, NP; 1 pt w partial remission; SD: 12 pts; Phase II: Cip/9NC, 60 mg/m2/1.25 mg/d or 40 vs. 2.0 | No 62 [183] |
| 2008 9-NC Phase II | po d1-5/wk* at 1.5 mg/m2/d; | Crystal powder in gelatin capsule, likely from Supergene Inc. | 19 pts w resistant metastatic head-&-neck cancer; SD: 3/13 pts & 10 progressed; 3 died shortly after treatment; DLT: anemia NP, TCP | No 63 [184] |
| 2009 9-AC Phase II | 72 h iv/2 wk*; 0.85 mg/m2/d (DMA); 1.1 mg/m2/d (CD) | Both DMA and CD formulations used (see No 2 and No 8) | 37 pts w relapsed lymphoma; OR rate: ~17% similar in both formulations; DLT: NP, anemia, TCP; serum drug level not link to response & toxicity | No 64 [185] |
| 2011 9-NC Phase I | po once at 1.25-1.75 mg/m2; then d1-5/wk at 1.5 mg/m2 | Capsules from Qilu Pharmaceutical Co., Ltd, China | 23 pts w advanced solid tumors; PK focused, no serous toxicity; There was 2-13 fold variabilities in 9-NC and 9-AC exposure among different pts | No 65 [186] |