Recurrence: VAL-083 or CCNU? Keytruda?

Hello all,

A few questions for my friend who is unfortunately having a recurrence.

1) Following surgery, is it better to go with VAL-083 since he is unmethylated or stick with CCNU since that is more the standard protocol for recurrent GBM? Any experiences with VAL-083 out there? 

2) Is the tumor genetic sequencing provided by the University of Pittsburgh considered the best, or should he request a Caris report?

3) Have any of you or your loved ones tried Keytruda pre-operatively to activate the immune system? How did you feel about it? Any significant side effects? 

For background purposes:

My friend was diagnosed in August 2018 - age 48. He had a total resection followed by SOC, Optune, supplements and 11 months of TMZ. A second tumor developed slowly  in the occipital area and was removed in November 2019. Unfortunately, the tumor recurred at the second site shortly after the surgery. However, following a second course of radiation and TMZ, it remained stable for six months. Avastin was used to control swelling and reduce tumor growth. In addition, a PARP inhibitor, Olaparib(Lynparza), was added after SOC as indicated by the genetic analysis. The tumor was unmethylated and IDH mutated.

The second tumor location recently started showing activity again. So a third surgery is planned in the next couple of weeks. We are looking at which chemotherapy to pursue afterwards and whether to use Keytruda before or after, as well. We have a friend that had a very positive response following a recurrence on the VAL-083 MD Anderson trial. He was unmethylated, as well, and has had clear scans for six months since completing VAl-083.

My friend was advised to stop using Avastin, although we have seen some studies that continued to use it in combination with CCNU. He is now age 50 with no deficits. He continues to use Optune. Any thoughts, experiences or pertinent studies relating to the chemo options for recurrence, VAL-083 and Keytruda would be greatly appreciated. We are grateful for the combined wisdom of Stephen and this community.

Best, 

Evelyn

Cocktail question, Fluoxetine or Celebrex?

Dear Stephen and all,

I have a question concerning my girlfriend's father. He is 57 years old. He was diagnosed with a Grade IV, MGMT unmethylated Glioblastoma in the left occipital lobe, September 2018. After the surgery, he received radiotherapy and chemotherapy using VAL-083 in China during 08/11/2018 - 27/06/2019. He had an MRI scan on 20/08/2019 and there is a 17mm*10mm GBM recurrence in the left temporal lobe.

Now his oncologist suggests receiving the standard 5/23 Temozolomide treatment. Since his GBM is MGMT unmethylated, we want to have the cocktail to enhance the performance of Temozolomide for him. He is taking Metformin, Verapamil, Chloroquine and Keppra. We want to choose 1 more medicine from Fluoxetine and Celebrex, which one is better?

Thank you for your help! Best wishes to everyone.

Details of the condition of my father are listed below:

• On 28/09/2018 he had surgery due to a tumor in the left occipital lobe. According to the biopsy, he was diagnosed with a Grade IV Glioblastoma Multiforme, MGMT unmethylated, ki67 70%, IDH1/2(-), 1p/19q non-codeleted, non-diffuse.
• On 08/11/2018, he began to receive radiotherapy and chemotherapy using VAL-083 with a dose of 30mg/m2 IV. But soon he suffered severe myelosuppression and both radiotherapy and chemotherapy are stopped for 2 weeks. After that, the dose of VAL-083 was tuned to 20mg/m2.
• On 24/06/2019, the assessment via MRI is CR I class, complete response (that shows the VAL-083 is effective for him)
• On 27/06/2019, he finished the clinical trial, including 10 cycles of treatment using VAL-083.
• On 20/08/2019, MRI shows that there is a 17mm*10mm enhanced mass in the left temporal lobe (the original tumor was in left occipital lobe).

Options for first recurrence

I’ve been following along here for the majority of my Dad’s 7 month long battle with gbm. I cannot express how grateful I am for the information, and for the people that contribute all that they do.  

We are looking at tumor recurrence for my Dad.  Our NO is Dr. Stupp and he was kind enough to reach out to UCSF, Dana Farber, Duke, and Mayo for second opinions/possible trial options since Northwestern did not have any other trials they liked for Dad. This is the email he sent out for us…

Diagnosis

Glioblastoma left temporal lobe

· s/p gross total resection on 5 May 2017.

· Histology:

· WHO, Grade IV, MGMT unmethylated, Ki-67, 30%.

· Gliaseq: EGFR ++, ATRX mutated,  copy number losses in CDKN2A and PTEN.

· Status post post NSC-adenovirus injection on 5 May 2017 (Phase 1 Protocol)

· Status post  TMZ/RT 30 x 2 Gy on 15 May – 26  June 2017 with concomitant TMZ

· status after 2 cycles of adjuvant TMZ.

Current Problem

· Suspected tumor recurrence at site of primary tumor location

o Contrast enhancement 1.5 cm approx., no edema, perfusion +, spectroscopy non-contributory.

· Adjuvant Optune™ treatment start suspended due to suspicion of recurrence.

Our Plan

·         Resection of contrast enhancing lesion in order to allow for

o    “Debulking” (not much bulk)

o    diagnostic clarification of post-therapeutic inflammation (warranted) and pseudo progression vs true recurrence

o    further second-line therapy in case of recurrence by either

§  ABT 414 (expanded access)

§  Irinotecan or other non-aklylating agent chemotherapy (unmethylated tumor, progressed under TMZ)

§  (CCNU)

§  other ?

add Optune as part of first line standard adjuvant therapy

I would imagine that’s a better summary than I could write. We’re hoping to find some input here because we have options open to us and we’re unsure which path to take.

Stupp initially advised surgery, but then our surgeon at Northwestern who we met with separately said he didn’t think the lesion was that dramatic and would prefer to wait 2 months to see on the next MRI what it looks like. He also felt with how well Dad is doing, and where the tumor is located, that surgery is too high risk for interfering with quality of life. Dad has not been on any meds (other than the temodar), goes to work daily, and has really not shown any new symptoms since his initial diagnosis.   He mainly just has some world retrieval issues, very minor comprehension issues, and a more difficult time reading and writing.

Duke, UCSF, and Dana Farber all said they may have trial options. Dr. Friedman did mention the polio trial was not an option, because they cannot do it in the left temporal lobe. 

Anyhow, coincidentally Dad already had trips to San Francisco and Boston planned back to back, so I joined him to meet with UCSF and Dana Farber. Both saw the scans and advised surgery to find out if this is recurrence or pseudo-progression. They also both recommended the Abemaciclib trial. I asked about MDNA-55 at UCSF, and they said the tumor board had discussed this, but had concerns. One was that Dad already participated in the NSC-adenovirus trial and they had no idea what this may look like or how it could behave in the brain, therefore their concern is that if it’s still active that there could be an unknown interaction with MDNA-55. At that time there was still the question of whether or not this was true progression as well, which is also why they hesitated on it. They did however send us home with a consent form, and left the option open.

In the time that has passed, we reached 4 weeks last Tuesday since the initial MRI, still without a plan of action. So I requested another MRI to which Stupp agreed. It showed the lesion was slightly more prominent, at 1.5 x 1.7 x 1.0 cm, formerly measuring 1.4 x 1.6 x 1.1 cm. There was also irregular curvilinear enhancement along the margins of the resection cavity. Stupp consulted our surgeon, and he still said no to surgery. So our option in Chicago is a second line therapy, as there are no more trials they have for Dad. I should mention that Dad has had no treatment of any kind  since Sept 3- his last day of temodar. He was delayed starting his 3rd cycle due to a work conference, then low platelets, then we had the MRI showing suspected recurrence so treatment was suspended. He does take a long list of supplements and some medical marijuana (which UCSF strongly supported when we met with them!)

Dad felt very confident with the team at UCSF and decided we should head there for treatment so we can participate in another trial. Stupp supports this, and advocated that Dr. Berger do the surgery if that’s recommended. We’ve been in touch with the NO there, Dr. Bush. She just revisited Dad’s case with the tumor board, and said that while MDNA-55 certainly could be done, based on the cystic component of his tumor, it is felt that the more aggressive option would be to do a surgery with a following clinical trial Abemaciclib, and that would be the approach they would favor.  When I showed Dr. Stupp both trials he also said he would favor abemaciclib.

I have thought all along that the MDNA-55 trial appeared to be more promising, and felt it could be a good opportunity. I also liked it because we could avoid resection, which Dr. Stupp said he’s not even sure if there is a survival benefit to multiple resections. Dad’s tumor is in an area where our surgeon in Chicago felt surgery could impede his speech/comprehension abilities. Whereas the surgeons at UCSF felt confident the surgery was low risk.  I’m sure you can tell that while we’re grateful for options, we are also a bit overwhelmed at making the right decision. Should we push for the CED of MDNA-55? Or should we simply trust in our doctors, who are all pushing us towards abemaciclib – which would involve another resection? I also know Dad would prefer not to be on a chemotherapy drug – but at the same time he is willing to do “whatever is best”. Of course we also still have the option of no surgery or trial at this time, and trying a different drug with Dr. Stupp. My concern with that is that we will miss an opportunity, while Dad is still very healthy and able to travel and participate in trials. 

I’ve hesitated posting here until I truly felt it necessary, as I very much appreciate the time and effort people put into this small community and have not wanted to utilize your time until we truly felt like we were at a crossroads. As such, I apologize for how lengthy this was. I just wanted to supply as much information as possible in hopes of finding some insight.  

Thanks so much,

Jaclyn

Expanded Access to VAL-083

https://clinicaltrials.gov/ct2/show/NCT03138629

"This is an expanded access program (EAP) for eligible participants. This program is designed to provide access to VAL-083 (dianhydrogalactitol) prior to approval by the local regulatory agency. Availability will depend on territory eligibility. Participating sites will be added as they apply for and are approved for the EAP. A medical doctor must decide whether the potential benefit outweighs the risk of receiving an investigational therapy based on the individual patient's medical history and program eligibility criteria."

There is also an upcoming phase 3 clinical trial that will test VAL-083 for recurrent GBM that failed Avastin.

https://clinicaltrials.gov/ct2/show/NCT03149575