Abstract
This thesis describes early clinical trials with anti-cancer drugs in combination with commonly applied and registered chemotherapy and single agent studies with compounds that are intended for use in combination with registered or other targeted anti-cancer drugs.
Gemcitabine is a prodrug that first needs to be metabolized in the body
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in order to exert its action. Fixed dose-rate infusion, an infusion at a lower speed, is a concept that takes into account the rate-limiting step of the activating enzyme deoxycytidine kinase (dCK). This new application of an existing drug was investigated in combination with carboplatin in ovarian cancer patients after first-line therapy and demonstrated that fixed dose-rate gemcitabine in combination with carboplatin in the applied schedule results in increased grade 3/4 toxicity compared to conventional 30-minute infused gemcitabine.
Ruthenium is a heavy metal like platinum and ruthenium derivatives have been developed with the objective to create drugs as powerful as cisplatin, but with limited adverse events. NAMI-A was the first ruthenium derivative that has been evaluated in a clinical setting, as a single agent. Promising preclinical results of the combination of NAMI-A and gemcitabine resulted in a clinical study with these two agents in non-small cell lung cancer (NSCLC) patients after first-line therapy. NAMI-A was moderately tolerated and expansion of the phase II part was not conducted because the predefined number of responses was not reached.
MEK inhibitors are an example of targeted anti-cancer drugs. MEK is part of the MAPK pathway. MAPKs are initiated by ligand binding at the cell surface and ultimately lead to gene transcription in the nucleus. Genetic alterations can lead to overexpression and aberrant activation downstream of the mutation. Selumetinib, a relatively older, second generation MEK inhibitor, was first developed as a mix and drink formulation. A food-effect study with a new capsule formulation with improved pharmacological properties demonstrated that the presence of food decreased the extent and rate of absorption of selumetinib.
A phase I study with the newer MEK inhibitor RO4987655 conducted in patients with different kinds of solid tumors defined the maximal tolerable dose (MTD) at 8.5 mg BID and demonstrated an acceptable toxicity profile.
MK-1775 is a selective inhibitor of protein Wee1, a key player in the G2 checkpoint and is thought to be especially active in cancer cells with p53 pathway mutations. Many tumors harbor p53 mutations, which make cancer cells more dependent on the G2 checkpoint for DNA repair. By inducing DNA damage with chemotherapy and pharmacological inhibition of Wee1 by MK-1775 apoptosis can be induced especially in tumor cells. A preliminary analysis of the first in human phase I study with MK-1775 in combination with gemcitabine, cisplatin or carboplatin showed that MK-1775 was well tolerated and has a developable pharmacokinetic profile. Preliminary results of the ongoing proof of concept phase II study in p53 mutated ovarian cancer patients after failure (during or within 3 months of treatment) of first-line therapy and treated with carboplatin plus MK-1775 are promising
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