P1446A-05 (a multi-CDK inhibitor) decreases melanoma growth especially when combined with MAPK inhibitors!

A novel multi-CDK inhibitor P1446A-05 restricts melanoma growth and produces synergistic effects in combination with MAPK pathway inhibitors.  Eliades, Miller, Miao, Flaherty, et al.  Cancer Biol Ther.  2016 Jan 25.

"Nearly 100% of melanomas have a defect in the p16^INK4A:cyclin D-CDK4/6:RB pathway, leading to abnormal cell cycle control and unregulated cellular proliferation. Here, we report that P1446A-05, a novel multi-CDK inhibitor has significant inhibitory activity against cutaneous and uveal melanoma. Mechanistic studies revealed that P1446A-05 inhibits phosphorylation targets of CDK members, and induces cell cycle arrest and apoptosis irrespective of melanoma genotype or phenotype. Additionally, we show preclinical evidence that P1446A-05 can synergize with other small molecule inhibitors previously studied in melanoma. Collectively, these data demonstrate that targeting cell cycle and transcriptional CDKs with a small molecule multi-CDK inhibitor is a viable approach for developing novel anti-melanoma therapeutics."

If you are wondering where CDK falls in the molecular lay of things...this diagram may help:  Melanoma pathways: melanoma molecular disease model

Early days with this one to be sure...but every bit of a good new thing....is a good new thing!!! - c

Nivolumab Shows Impressive OS in melanoma

Nivolumab shows impressive long term overall survival in melanoma  

Single-agent nivolumab (Opdivo) demonstrated a robust 5-year overall survival (OS) rate of 34% for heavily pretreated patients with metastatic melanoma who had not received prior ipilimumab (Yervoy), according to long-term findings from a single-arm phase I study presented at the 2016 AACR Annual Meeting.

Findings from the study, which began enrolling patients in 2008, represent the first report of long-term outcomes from a clinical trial exploring a PD-1 inhibitor. In the study, the 5-year survival rate with nivolumab was double survival statistics from the SEER database. From 2006 to 2012, the database lists a 5-year survival rate of 17.9%.

“These data represent the longest survival follow-up of patients who received anti–PD-1 therapy in a clinical study, and suggest durable, long-term survival with nivolumab monotherapy,” said lead investigator F. Stephen Hodi, MD, director of the Melanoma Center at Dana-Farber Cancer Institute. “Nivolumab continued to be safe and tolerable, with no deaths or new safety signals”

In the study, which was labeled CA209-003, 107 patients received nivolumab across 5 dose levels every 2 weeks. Doses were escalated from 0.1 mg/kg to 10 mg/kg and were continued for greater or equal to 96 weeks. The primary endpoints were safety and tolerability with secondary outcomes focused on efficacy, with an amendment to the original protocol to assess long-term OS.

The median age of patients was 61 years, and most had an ECOG PS of 0 or 1 (97%). Sixty-two percent of patients had received ≥2 prior therapies, including 46% who received prior interleukin-2. Overall, 78% of patients had visceral metastases at baseline and 36% had elevated LDH levels.

After a minimum follow-up of 45 months, median OS was 17.3 months (95% CI, 12.5-37.8). According to the Kaplan-Meier curves, the median survival plateaued at month 48, with a follow-up duration of 80 months for some patients. At 30 months, the progression-free survival (PFS) rate was 18.6%.

In those treated specifically with the 3-mg/kg dose of nivolumab (n = 17), which is the FDA-approved dose, the median OS was 20.3 months (95% CI, 7.2-NR). The 5-year OS rate was 35.3% and the 30-month PFS rate was 25.7%.

“In all patients, there is a plateauing, a so called tail on the curve, and it’s lasting many months to years, and about a third of patients have this long-term survival,” said Hodi. “Those who make it to 48 months, have a very good chance of surviving their disease.”

An exploratory analysis looked at patients who were retreated with single-agent nivolumab. Patients were eligible for retreatment if they had initial disease control and subsequent progression, no dose-limiting adverse events (AEs), and went 1 year without progressive disease. Patients restarted nivolumab at the same dose originally assigned for up to a total of 3 years including the initial treatment period.

Five patients who were off treatment for 100 days experienced durable disease control with nivolumab retreatment. One patient in this group, who remains on treatment, had adrenal metastasis that was excised, resulting in no evidence of disease and a long-term benefit.

“Updated analysis of retreated patients showed that disease control was maintained,” said Hodi. “This demonstrates the importance of the durability of clinical benefit for patients; now, we are measuring in terms years. As well as the memory aspect, how the immunologic memory translated to better outcomes.”

Across all dose levels, 84.1% of patients experienced an AE, with 23.4% being grade 3/4 in severity. At 3 mg/kg, all-grade AEs were 88.2% and grade 3/4 AEs occurred in 35.3% of patients.

The most common nivolumab-related all-grade AEs across doses were fatigue (29.9%), rash (23.4%), diarrhea (17.8%), pruritus (13.1%), and nausea (8.4%). AEs led to treatment discontinuation for 10.3% of patients. The most common grade 3/4 AEs were lymphopenia (2.8%), fatigue (1.9%), diarrhea (1.9%), and nausea (0.9%).

Initial findings from the phase I study, which also enrolled patients with renal cell carcinoma (RCC) and non–small cell lung cancer (NSCLC), ushered in a new era focused on immunotherapy. Following a presentation of the results at the 2012 ASCO Annual Meeting, a number of larger studies were initiated, which quickly led to approvals for nivolumab across a variety of settings based on phase III studies.

“What distinguishes immunotherapy from other forms of cancer treatment is the durability of the benefit. Those who have complete responses seem to be protected from that disease recurring,” said Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center, who moderated a press conference. “The memory and the adaptability of the immune response to pick off resistant variables is an important take-home here. These are very compelling data to suggest that this is the case.”

Nivolumab is currently approved as a single-agent and in combination with ipilimumab for patients with metastatic melanoma. Additionally, the agent is approved for patients with non-squamous and squamous NSCLC and for those with metastatic RCC.

An application to further expand nivolumab's indication is currently pending with the FDA, for use of the PD-1 inhibitor to treat patients with classical Hodgkin lymphoma, with a decision expected in the second half of 2016. Additionally, an application will be filed within the coming months for the agent as a treatment for head and neck cancer, based on an extension in OS in a phase III study.

Can't really be hat'n on this bizness!!!  There was this from back in the day:  Survival curves for Stage IV melanoma  In 2012, Weber and Sznol were chatt'n about this: Weber and Sznol chat about ipi and anti-PD1  Here is an ASCO 2013 report on OS with NIVO: Long overall survival in melanoma patients treated with Nivo 

My last dose of nivo was in June of 2013.  This study was pre-me and my ratties.  And....you have to remember that my ratties and I were in an NED arm vs an active disease arm...all of us immunotherapy naive, in an escalating dose plan with the first 10 of us getting 1mg/kg (this was my group), the next getting 3mg/kg, and the last additional 10 getting 10mg/kg.  Many, many arms were added later...but this is how we began...and we're hang'n in there pretty well.  Way to go ratties!!! - c

PS.... this was in my lunch today...."I be ride'n the tail!"  Yes, my lunch is packed daily...not by me.  Has been. Always.  Even when I worked night shift.  I arrived at work with grocery bags full of pop tarts, sandwiches, Dinty Moore canned stew...with the label crossed out with "Les is Moore" hand written in.  Yes, I ate it all.  It kept me awake and therefore, my patients alive.  And the lunches always...always...included a note.  Of  course my nurses, who now snatch up the note even before I see it, thought today's note salacious.  At first....I was just confused.  But then....light dawned.  We got the curve by the tail...mister.  You'd better hang on! ~ les

Sew Chaotically! - and Appalachian spring beauties....

...in my own backyard!

Wood Poppies

Bleeding heart

Fairy Pagodas....yeah, yeah....I know they are May apples...but I prefer Fairy Pagodas!!!

Virginia Blue Bells

Wild Azalea

Jacob's Ladder

Thyme Leaved Bluets down by the creek.

Crested Dwarf Iris

Nature's random plantings are so much better than any we can contrive!

My beautiful cherry trees...planted by B....that time when I almost made it 5 years NED!!!  2003 to end of 2007.  BUT....you should see what's he's planting now!!!  2010 - TODAY!!!!!

Then, just for spring sewing fun.....there was this: 

A bright crazy knit elastic waist skirt just because!

I thought I did some good side seam matching....considering!

A tale of two tops!

Mine...

And Roo's....It is just so easy and fun to sew up this top.  And I had extra material...and Rosie has always loved the floral print that has long lived in my fabric stash....so...  Plus, I made her another little stretch corduroy skirt since she had worn out the purple one I made her a year ago!!  Don't know if she'll wear them as a set.....but she's got options...

And so exciting!!  She finally got her 'real' bedroom set up with the quilt and curtains I made her here:   Sew Chaotically! home decor

Hoping your spring is beautifully chaotic!!!  Much love, c

TILs (tumor infiltrating lymphocytes) - advancing as melanoma immunotherapy and new trial

After nearly 30 years of research, tumor-infiltrating lymphocyte technologies are being investigated as a means of producing personalized immunotherapy for patients with metastatic melanoma in a small clinical trial that may help open the door for broader application in other solid tumor types.

http://www.onclive.com/publications/oncology-live/2016/vol-17-no-7/tils-advancing-as-melanoma-immunotherapy-option/2

[In an interview] Weber said acute toxicities that have been associated with TIL therapy include hemorrhagic cystitis, cytoxan-induced syndrome of inappropriate antidiuretic hormone, neutropenic fever/ sepsis, and hypotension/capillary leak. He said researchers have adjusted to these toxicities by limiting IL-2 to 6 doses after TIL infusion therapy. Chronic toxicities have included fatigue, neuropathy, vitiligo, and uveitis.

One key challenge in TIL therapy that has been partially overcome, Weber said, is finding a better way to grow TILs. The process used to take 6 or more hours, multiple incubators, and multiple technicians. Today, he said, with the use of bioreactors and a closed system, the process is more efficient and only requires one technician. There is still more work to be done to make the process even better, he noted. The approach is moving forward in the phase II, multicenter LN-144 study, which aims to assess the safety, feasibility, and antitumor activity of this treatment followed by IL-2 for patients with metastatic melanoma who are refractory to at least one systemic therapy.³ Researchers are seeking to enroll 20 patients.

For trial inclusion, patients must have measurable disease with at least one lesion that is resectable for TIL generation; that is, at least 1.5 cm in diameter and able to be removed with minimal morbidity. Exclusion criteria include prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen, more than three brain metastases, and current use of a systemic steroid regimen.

This trial is an exciting early step, according to Steven A. Fischkoff, MD, chief medical officer of Lion Biotechnologies, Inc, a New York City–based company that is developing the TIL therapy under an orphan drug designation. He said that focusing on TILs is a forward-looking approach to immunotherapy. Weber, who is a member of Lion’s scientific advisory board, said the technology holds promise for a variety of tumor types. Besides melanoma, other cancer types that might prove amenable to TIL therapy include renal cell carcinoma, ovarian cancer, glioblastoma multiforme, lung cancer, and cervical cancer, he said.

“You can definitely grow TILs from a variety of tumors,” Weber said. “In the old days, people tried to do it and couldn’t figure out what to do. It turns out to be much easier to do than we thought.”

TIL therapy is tough.  I've lost some dear to me after they tried it.  On the other hand...when it works....it is amazing.  It makes sense.  It holds promise.  Not sure how benign and dependable it has really become....that's what the amazing ratties who sign up for this trial will show us.  Fingers crossed for everyone. -c

Melanoma does not discriminate! Here's proof:

This summary is not available. Please click here to view the post.