Phase I clinical trial of melphalan and 41.8 degrees C whole-body hyperthermia in cancer patients.
OBJECTIVE
To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes.


METHODS
Sixteen patients with refractory cancer were treated (May 1992 to May 1995) with WBH alone during week 1) thereafter patients were randomized to receive either L-PAM alone on week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patients who demonstrated clinical improvement received WBH plus L-PAM monthly. Dose levels of L-PAM were 10 mg/m2 (n = 3), 15 mg/m2 (n = 3), 17.5 mg/m2 (n = 6), and 20 mg/m2 (n = 4). L-PAM was administered at target temperature; WBH was administered with an Aquatherm radiant-heat device (patent pending; Cancer Research Institute, New York, NY).


RESULTS
Comparisons of mean WBC count and platelet nadirs for L-PAM alone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no instances of febrile neutropenia or bleeding. Toxicities allowed for escalation of L-PAM to 20 mg/m2; all four patients at this level experienced grade 4 myelosuppression. No significant myelosuppression was observed at 10 and 15 mg/m2. Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m2. Responses included complete remission (CR) of pancreatic cancer (10 mg/m2), partial remission (PR) of malignant melanoma in two patients (20 mg/m2), and transient clinical and/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is also discussed in detail.


CONCLUSIONS
We conclude that L-PAM with 41.8 degrees C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress.
Robins
H I
HI
University of Wisconsin Comprehensive Cancer Center, Madison, USA. HIRobins@FACSTAFF.wisc.edu
Rushing
D
D
Kutz
M
M
Tutsch
K D
KD
Tiggelaar
C L
CL
Paul
D
D
Spriggs
D
D
Kraemer
C
C
Gillis
W
W
Feierabend
C
C
Arzoomanian
R Z
RZ
Longo
W
W
Alberti
D
D
d'Oleire
F
F
Qu
R P
RP
Wilding
G
G
Stewart
J A
JA
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D013696:Temperature; D014839:Vomiting / Q000139:chemically induced
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D008558:Melphalan