New Drugs on the Blog — Monday 6/1

Post by Archie N. Tse, MD, PhD:

Beyond mTOR1 – new PI3K Kinase Pathway Inhibitors. The Clinical Science Symposium this afternoon focused on PI3K/Akt inhibitors. Given the critical role of PI3K/Akt in cell proliferation and survival, and how frequently this pathway becomes dysregulated in human cancers, the stakes are generally high for this class of agents. So, did PI3K/Akt inhibitors live up to our expectations?

The first presentation was by Shapiro et al. (#3500) on XL147, a pan-PI3K inhibitor. The MTD was determined to be 600mg PO once daily for 21 days in a 4-week cycle. Two DLTs were seen at 900mg (G3 skin rash). Dose escalation for the continuous dosing schedule is on-going. Pharmacodynamic studies performed on hair follicles and paired tumor biopsies (n=6) showed that up to 70-80% suppression of p-Akt and p-4EBP1 could be seen following drug treatment, although inhibition of Ki67 (a proliferation marker) was only 20-30% and apoptosis was absent. One NSCLC pt had a PR and 37% of pts had SD for >=12 weeks with 1 pt showing a drop in PSA.

Wagner et al. presented the phase I results of GDC0941, another panPI3K inhibitor (#3501). Escalating doses were given once daily or bid in parallel cohorts. The MTD of the once daily schedule was reached at 100mg. DLTs were G3 headache and pleural effusion. It was unclear whether the latter was treatment-related. Other toxicities include nausea, vomiting, and thrombocytopenia. Pharmacodynamic studies showed reduction in pAkt in platelet enriched plasma. Stable disease was the best treatment response.

The third pan-PI3K inhibitor was XL765 presented by LoRusso et al. (#3502). Unlike XL147, XL765 also inhibits TORC1, and to some extent TORC2, in addition to PI3Ks. Forty eight pts were enrolled. The MTD is 50mg for bid dosing and 70mg for daily dosing. DLTs were LFT elevations, rash, anorexia, hypophosphotemia, and nausea/vomiting for bid dosing; and dyskinesis and rash for daily dosing. Common toxicities were mainly GI. Interestingly hyperglycemia has not been a major concern for all 4 agents studied although transient hyperinsulinemia was seen. Inhibition of PI3K and Akt signaling was demonstrated in surrogate and tumor tissues. Compared with XL147, suppression of Ki67 by XL765 was somewhat higher and apoptosis was also slightly more prominent. Six patients had SD for >=16 weeks.
Perhaps the “cleanest” inhibitor presented today is the allosteric Akt inhibitor MK2206 (Tolcher et al. #3503). It is not an ATP-mimetic but it prevents localization of Akt to the plasma membrane to be activated. Thirty four pts were enrolled. The MTD is 60mg orally qod. DLTs were G3 skin rash at both 75 and 90mg. Again, no PR was seen but there was some hint of activity with a pt with neuroendocrine tumor showing less ascites and an ovarian pt having a CA125 decline.

Obviously, these results raise more questions than answers. The fact that we had only 1 PR overall may sound discouraging. However, in the absence of any genotyping data, I think these results are preliminary at best. Perhaps cytostasis is what we should expect from this class of drugs. One should stay tuned for more single agent as well as combination studies of PI3K/Akt inhibitors.

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New Drugs on the Blog – Sunday May 31

Post by Archie N. Tse, MD, PhD:

Today is relatively quiet for Developmental Therapeutics. In the Cytotoxic Chemotherapy Oral Presentation Session, Hamada et al. studied the pharmacogenetics of the EFGR antagonist erlotinib, specifically the association of erlotinib PK and ABC efflux transporter polymorphisms with drug toxicity in Japanese NSCLC patients (pts). It has been reported that 1236C>T, 2677G>(T/A), and 3435C>T single nucleotide polymorphism in ABCB1 are associated with reduced protein expression. In 22 pts, the AUC and Cmax of erlotinib on Day1 correlated with the severity of skin rash. All Patients (n=4) with homozygous variant for ABCB1 1236TT- 2677TT/TA/AA-3435TT showed a higher steady state Cmin and also developed grade≥2 skin rash, suggesting that ABCB1 gene polymorphism may explain the variable toxicity and PK to erlotinib.

BSI-201 is no doubt a pleasing surprise at the Plenary Session. My breast oncology colleague will probably cover this as well but I feel complied to report this abstract (#3) as it is conceptually related to my own research. O’Shaughnessy et al. presented a randomized phase II study of gemcitabine/carboplatin with or without BSI-201, a poly(ADP)ribose polymerase (PARP) inhibitor, in metastatic triple negative breast cancer (TNB) pts. TNB (ER/PR/Her2-negative) to some extent resembles Brca1-deficient tumors. Strong pre-clinical data have suggested that Brca-deficient cells are selectively more sensitive to PARP inhibitors. One hundred and sixteen pts were assigned to receive either chemotherapy alone or chemotherapy and BSI-201 at 5.6mg/m2 iv TIW x 2 weeks every 21-days. There was no increase in chemotherapy-related toxicity in the combination arm – an exceptional finding. The primary study endpoint was met, i.e. clinical benefit rate, defined as CR+PR+SD ≥6 months. Approximately 62% of pts receiving the combination showed clinical benefit, compared with 21 % in the control (p= 0.0002). Tumor response, PFS, and OS were all superior in the BSI-201 arm (48 vs 16%, 6.9 mo vs 3.3 mo, and 9.2 vs 5.7 mo, respectively). These results highlight the therapeutic potential of DNA damage response modulators.

New Drugs on the Blog

Post by Archie N. Tse, MD, PhD:

There will be more coverage on PI3K/Akt inhibitors at the Clinical Science Symposium on Monday but I think these 2 posters are worth mentioning. Flinn et al. presented the first-in-man study of CAL-101, a PI3K isoform-specific inhibitor with ≥40-fold selectivity against the p110d isoform that is expressed primarily in hematopoietic cells (#3543). 12 patients (pts) with hematological malignancies were enrolled (6 CLL and 6 NHL). Side effects were mild and no DLT was seen up to 350mg PO bid. Clinical activity was seen in 6/12 of this heavily pre-treated group of pts (PR in 2CLL, 2 mantle cell, and 1 follicular lymphoma). Dose escalation is still on-going. F1126 is the prodrug of the well known pan-PI3K inhibitor LY294002 conjugated to an RGD targeting peptide (#2558 Chiorean et al.). The drug was safe up to 1100mg iv biw with 1 DLT (G3 diarrhea) at 180mg. Toxicities were mainly gastrointestinal and some manageable infusion-related side effects. No consistent hyperglycemia was seen. Sixteen of 36 pts had stable disease. Evidence of target inhibition (pS6) was seen in tumor biopsies in 1 pt.

What’s new in Apoptosis-Targeting Drugs? We have learned at the Clinical Science Symposium on Sat that the Bcl2 antagonist Oblatoclax (GX15-070MS) at 14mg/m2 iv days 1 and 3 can be combined with topotecan at 1.25mg/m2 iv days 1-5 with acceptable toxicity (#3504; Brown et al.). Myelosuppression and transient neurological dysfunction were common AEs. There were 2 PR in NSCL and 4 SD in 15 pts. We also learned that the mechanistic-based acute thrombocytopenia and platelet count fluctuation induced by the other Bcl2 antagonist ABT263 could be ameliorated by lowering the lead-in dose to 150mg and using a continuous dosing schedule (#3505; Roberts et al.). LY2181308 is an anti-sense oligonucleotide against survivin, an inhibitor of apoptosis and mitotic regulator (#3507). Talbot et al. did some nice pharamcodynamic studies on pre- and post-treatment tumor biopsies as well as endobronchial samplings showing that survivin gene and protein can be reduced by LY2181308. The key question is how much survivin knockdown will be necessary to produce a therapeutic effect.

The Met/Alk RTK inhibitor PF02341066 grabbed the lime light at the Molecular Therapeutics Oral Presentation (#3509; Kwak et al.). About 4% of NSCLC express an aberrant Alk fusion protein (Eml4-Alk most common), making them susceptible to Alk inhibition. The MTD of PF02341066 is 250mg po bid. DLTs were one G3 ALT and two G3 fatigue. Common AEs were nausea, vomiting, diarrhea, and fatigue. One pt with inflammatory myofibroblastic tumor harboring Alk rearrangement had a PR. Remarkably, in an expansion cohort of NSCLC pts with ALK rearrangements, 10 of 19 had a PR and 5 had SD. Molecular genetics of NSCLC is increasingly more heterogeneous.

In the same session, Schwartz et al. presented a phase I study of XL281, a pan-Raf kinase inhibitor (#3513). Thirty solid tumor pts were treated during dose escalation. The MTD is 150mg po daily. DLTs of fatigue, nausea, vomiting, and diarrhea were observed at the MAD (225 mg). Most common AEs were fatigue, diarrhea, nausea, vomiting and anorexia. One pt with ocular melanoma had a PR. The MTD was expanded to 10 pts each with colorectal, melanoma, papillary thyroid (PTC) and NSCLC. Nineteen pts had SD with minor responses in PTC pts. pErk down-regulation was shown in tumors in 3 pts independent of BRAF V600E and N-ras status, indicating that target inhibition is likely required but insufficient to produce a response. Of note, in situ SCC and keratoacanthoma were reported in 4 pts.

New Drugs on the Blog

Post by Archie N. Tse, MD, PhD

Experimental therapeutics at ASCO this year starts off with a Poster Discussion Session. Several abstracts are quite interesting. Just to name a few:

It looks like targeting angiogenesis has moved beyond anti-VEGF therapy. We know that tumors can develop acquired resistance to anti-VEGF treatment by up-regulating other pathways of angiogenesis, providing the rationale for combination therapies. Carducci et al presented a phase I study of bevacizumab (Bev) in combination with enzastaurin (Enz), an oral inhibitor of the PKC and PI3K/Akt pathway with anti-angiogenesis properties (#3517). Fifty four patients (27 ovarian) were enrolled. The combination was well-tolerated up to Enz 750mg bid x 21days and Bev 15mg/m2 iv on Day1 without any cycle 1 DLTs. The regimen is clearly active with 2 CR and 8 PR total, and 7 PR in the ovarian subset. Stay tuned for more Bev combo studies.

Clinical activity of some “promiscuous” multi-targeted kinase inhibitors is hard to deny. Thirty seven patients with advanced iodine-insensitive differentiated thyroid cancers including papillary, follicular, and Hurthle cell histologies were treated in a phase II study of pazopanib (GW786034), an inhibitor of VEGFR, PDGF, C-kit, and RET. Given at 800 mg PO daily, the drug was not only well-tolerated, its clinical activity was impressive with 12 patients achieving PR by RECIST (#3521, Bible et al.).

Inhibition of the molecular chaperone Hsp90 causes degradation of multiple client proteins that are critical for tumor growth and survival. AUY922 and alvespimycin (17DMAG) are two structurally distinct Hsp90 inhibitors studied in phase I. Sessa et al reported that AUY922 given iv once weekly was well-tolerated between 2-54mg/m2 (#3532). Most common AEs include asthenia, fatigue, nausea, and vomiting. Grade 1-2 reversible visual symptoms were also reported at 40 and 54mg/m2. Dose-dependent induction of Hsp70 in PBMC was seen. As with most Hsp90 inhibitors given as single agents, no response per RECIST was seen although metabolic response (≥25% reduction in SUV) by FDG-PET was observed in 5 patients. The significance of these PET responses has yet to be determined. Pacey et al reported that 17DMAG was well-tolerated up to 80mg/m2 given iv once weekly (#3534). Pharmacodynamics of Hsp90 was demonstrated in both PBMC and some tumor biopsies. Two PRs were seen, 1 prostate cancer and 1 melanoma. One may argue that Casodex withdraw may account for some of the response in the prostate patient; nonetheless, seeing single agent activity with an Hsp90 inhibitor is very interesting.