Biomodulatory metronomic therapy in stage IV melanoma is well-tolerated and may induce prolonged progression-free survival, a phase I trial.

Generally, redirecting hallmarks of cancer by communicative reprogramming leads to long‐term tumour control in histologically quite different neoplasias1, 2: A recently published randomized phase II trial on metastatic melanoma revealed significant impact of pioglitazone, a peroxisome proliferator‐activated receptorγ (PPARγ)3, 4 agonist, on inflammation control, progression‐free survival and overall survival when added to immune‐modulatory and angiostatic acting metronomic low‐dose chemotherapy.5, 6, 7

In the present phase I trial we studied tolerability and efficacy of the original combination pioglitazone daily 60 mg p.o, etoricoxib daily 60 mg p.o., plus low‐dose trofosfamide daily 50 mg three times p.o., and supplemented temsirolimus i.v. weekly at two dose levels, cohort 1, 15 mg, cohort 2, 25 mg (PETT schedule) (Fig. 1).8, 9 All medications were given continuously from day 1 until progression.

Figure 1

Hepatomegaly due to far advanced diffuse and multifocal metastases in patient No. 5 (Table 1) with uveal melanoma. Hepatomegaly did not decrease during PETT therapy, but disease could be stabilized for 1 year paralleled by a steep decrease of MIA in serum (Table 1).

Table 1

Characteristics of patients enrolled in phase I part of the study

Patient no/age (year)	Histology, initial stage	Prior treatment	Clinical status before	Metastatic sites at study inclusion	Treatment duration (months)	Best response/tumor marker initially	Grade 3/4 toxicities following phase I (NCI‐CTCAE version 4.0)	Overall survival (months)/outcome
1/68 y	Primary metastatic melanoma Stage IV	IFNα, 9 months Radiation left axilla 60 Gy, Radiation 60 Gy paravertebral left	ECOG 0	‐ Axilla left ‐ Chest wall left (per continuitatem lung)	8	SD MIA 16/21 ng/mL	‐ Neutropaenia 3 ‐ Anemia 3	13 Progression in the radiation field
2/83 y	Mixed desmo‐plastic melanoma Glandula parotis pT4 pN1a	R0 resection	ECOG 1	‐ Mandible and parotis right ‐ Lung right ‐ Liver Seg VII/VIII and diffuse infiltration	9 MIA 8.1–8.5	SD S‐100 0.45/0.1 μg/L	No	14 Progression at metastatic sites
3/71 y	Uveal melanoma right eye, (metastatic) T3, N0, M1c Stage IV	Local proton therapy SIRT therapy: Right hepatic lobe	ECOG 0	‐ Multiple liver lesions Seg IVb/III and diffuse liver infiltration	13	PR MIA 8.6/8.5 ng/mL	‐ Edema 3 ‐ Supra‐ventricular tachykardia (SAE) ‐ Synkope (SAE) ‐ Pain left arm ‐ Neutropaenia 3	20 Progression liver
4/71 y	Superficial spreading melanoma dorsal, pT1a, R0, N0, M0, Stage Ia	For metastatic disease: Radiation of thoracic vertebra 11 and chest wall	ECOG 0	‐ Adrenal gland, per continuitatem kidney right ‐ Superficial spreading melanoma ‐ Bone metastases	4 Inhibition of further spreading	SD MIA 22/23 ng/mL	Perianalnumbness, Anal and urinary incontinence: ‐ Anaemia 3 ‐ Leukopaenia 3	8 Progression in the radiation field and vertebra 11
5/79 y	Uveal melanoma, (right eye, metastatic) Multiple liver metastases Stage IV	Silikonoil tamponade	ECOG 2	‐ Seg V/VI, III and diffuse infiltration ‐ Bone metastasis left femur	12	SD MIA 465/82 ng/mL	‐ Anaemia 3 ‐ Edema 3 ‐ Dehydration 3	13 Progression at original metastatic sites
6/86 y	Melanoma DIG II left pT2a N3 M0 R0, Stage IIIb	Excision, coverage with allo‐plastic material Systematic lymph‐adenectomy left groin level I and radiotherapy left groin	ECOG 0	‐ Lymphnodes left iliacal, paraaortal ‐ Pericardial effusion, pericardial tumor, per continuitatem lung ‐ Skin involvement	5	Mixed response S‐100 0.45/0.1 μ/L	No	14 Progression in the radiation field

ECOG, Eastern Cooperative Oncology Group performance status; SIRT, selective internal radiation therapy; MIA, melanoma inhibitory activity; SD, stable disease; PR, partial response; SAE, severe adverse event.

Main inclusion criteria were age >18 years, histologically diagnosed metastatic melanoma with BRAF (the human gene that codes for the serine/threonine protein kinase B‐Raf) wild‐type, and LDH level >0.8 ULN, measurable lesions, and subjects had to receive study medication as first‐line therapy.

Dose‐limiting toxicity (DLT) was defined as any toxicity within the first 3 weeks of treatment with CTCAE (NCI‐CTCAE version 4.0) grade ≥3 and a causal relationship to the administration of one of the study drugs. At the end of phase I, patients were followed according RECIST criteria for progression‐free and overall survival. Computed tomography or magnetic resonance imaging (RECIST criteria) was performed every 8 weeks. The trial is approved by the local ethic committee and registered at ClinicalTrials.gov (NCT01614301).

Six elderly female patients (68–86 years old) with stage IV melanoma of uveal (n = 2) or cutaneous origin (n = 4), diffuse and multifocal liver metastases (n = 4) or tumour growth per continuitatem (n = 2) were enrolled during phase I. Local pretreatment and metastatic sites at study inclusion are listed in Table 1.

The 25 mg dose of temsirolimus was chosen for the randomized phase II part of the study as no DLTs occurred in cohort 1 or 2. Two severe adverse events (SAEs) were observed during phase I part of the study, one due to pneumonia and another to pleural effusion. Both SAEs resolved during continuation of study medication. Grade 3 (no grade 4) toxicities during the follow‐up phase are listed in Table 1. According to scheduled dose reductions, trofosfamide was reduced to 50 mg twice daily in four patients. Due to oedema, the dose of pioglitazone was reduced to 30 mg daily in two patients.

Progression‐free survival was 4–13 months, with four disease stabilizations, one mixed response (no objective response in the radiation field) and one partial response (PR) (Table 1). One stable disease in a patient with diffuse as well as measurable liver metastases of uveal melanoma was associated with a steep decline of melanoma inhibitory activity (MIA) and an improvement of Eastern Cooperative Oncology Group (ECOG )status from ECOG 2 to 1 (Fig. 1, Table 1). PR was not associated with a significant decline of MIA (Table 1). Interestingly, two patients with extensive metastatic liver involvement from uveal melanoma had a comparatively long progression‐free survival.

In all patients, progression took place at the original metastatic sites. Patients, who were prior irradiated, presented with progression in the radiation field.

To our knowledge, this is the first report describing the use of PETT schedule, to successfully control both, metastatic growth in cutaneous and uveal melanoma by simultaneously targeting multiple hallmarks of melanoma: Communicative reprogramming may overcome (molecular‐)genetic heterogeneity among melanomas of quite different origin as well as at different metastatic sites.2, 5 PETT schedule provides a modest toxicity profile and omits maximal tolerable dosages of single drugs by concertedly modulating melanoma plus adjacent stroma cell functions.3, 5, 8, 10 These promising data with PETT combination therapy are currently studied in a randomized phase II trial in second‐line.

A.R., C.H. designed the research, analysed the data and wrote the paper; C.H., M.V., Ch.H., M.L., M.B., S.H. and A.R. treated the patients; W.H. critically reviewed the manuscript.