Capivasertib Intolerance and the Next-Generation PI3K/AKT Trials: What's Actually Open Right Now

If you've been on capivasertib (Truqap), or another PI3K/AKT/mTOR pathway inhibitor, and had to come off — not because it wasn't effective, but because the hyperglycemia, the diarrhea, the rash, the fatigue became unbearable — then it's time to discuss the current trial landscape and decide if it's time to self-advocate.

Stopping a drug due to intolerable side effects is not the same as the drug failing you. It's the drug's design failing you.

The Off-Target Problem

Capivasertib doesn't just hit the AKT protein in your cancer cells. It hits AKT everywhere in your body — in your liver, your fat tissue, your kidneys, the cells that regulate your blood sugar. That's not a side effect of your biology being fragile. That's the drug's non-selective mechanism doing exactly what it was built to do, just in more places than anyone wanted. This is why so many women describe glucose spiking within days of starting, kidney markers shifting, a bone-deep exhaustion that doesn't lift on the "off" days. It's not you. It's an overshoot.

Newer drugs in this exact same class are being engineered specifically to fix this problem — mutant-selective PI3K and AKT inhibitors designed to hit only the cancer-relevant mutation and leave your normal tissue alone. Early data on some of these shows patients with far less fatigue and hyperglycemia, on drugs targeting the same pathway that made so many of us sick. The solution already exists in early trials. The problem now is access.

"From the outside it can look like 'if I meet the criteria, I can get in'. What I've seen instead is that there might only be one or two actual spots at each site, even on a big global trial. A 400-patient trial sounds huge until you realise that's the entire world's allocation. It makes these studies feel less like options on a menu and more like a lottery with very few winning tickets." — Group member, living with metastatic HR+/HER2- breast cancer

The Access Wall — And Why It's Not As Solid As It Looks

Here's what almost no one tells you when you're handed the diagnosis and see the drug line: many of the newer, better-tolerated trials in this drug class require you to have never taken a PI3K, AKT, or mTOR inhibitor before. Not "never taken it successfully." Never taken it, period. If you tried capivasertib for six weeks and your glucose skyrocketed and your doctor pulled you off it to protect your kidneys, you may find yourself excluded from some trials designed to spare the next generation of patients from that exact experience.

But — and this is the important correction to earlier drafts of this piece — this is not universally true across every trial in this class. When we actually pulled the current, live eligibility criteria from ClinicalTrials.gov rather than relying on secondary summaries, the picture split clearly into "locked out," "ambiguous," and "genuinely open." That distinction matters enormously for where you spend your energy and your oncologist's time.

This isn't a moral judgment on trial designers who do exclude prior-treatment patients. Comparative trials need clean populations to prove a new drug is better than the old one. That's real science. But it does mean some women — the ones who already paid the price of finding out the old drug doesn't work for their body — are excluded from certain newer trials, through no fault of their own, simply because of when their diagnosis and treatment history happened to line up. The encouraging news is that this isn't the whole story.

"One thing I wish I'd understood sooner is that eligibility isn't just 'yes or no on paper'. Even when the listing says 'recruiting', my centre might not have any slots allocated to them, or they may already have a long waitlist. I'm number seventy-seven on one trial's list. Realistically, I will never be called. That's not written anywhere in the criteria, but it completely changes what's actually possible." — Group member, living with metastatic HR+/HER2- breast cancer

What We Actually Verified: Three Trials, Three Different Answers

TOS-358 (NCT05683418) — Confirmed Open to Breast Cancer Patients With Prior Exposure

TOS-358, from Totus Medicines, is an oral, covalent PI3Kα inhibitor — meaning instead of binding and releasing the target protein like most drugs, it forms a permanent chemical bond to the mutant PI3Kα protein specifically. This lets it achieve over 95% continuous target suppression at low doses while staying alpha-selective, largely sparing healthy tissue elsewhere in the body.

The critical detail: the trial's actual exclusion criteria state that prior treatment with a PI3K, AKT, or mTOR inhibitor is only disqualifying "for non-breast cancer" patients. Read plainly, that means breast cancer patients are not excluded on the basis of prior AKT/PI3K/mTOR exposure at all. This is not a maybe, and it's not something that needs a speculative email to test — it's stated in the live, official criteria.

Early Phase 1b data (56 heavily pre-treated patients, presented in 2026) showed markedly better tolerability than older drugs in this class, with hyperglycemia present but far more contained — only 2 of 56 patients needed ongoing insulin, and both already had elevated BMI going in.

The catch: current recruiting sites are in the US (Los Angeles, Chicago, Boston, Oklahoma City, Philadelphia, Nashville, Fairfax VA) and Spain — there are no confirmed UK, Australian, or Canadian sites as of this writing. For a woman in the UK or Australia, this is a "genuinely eligible, but a travel and logistics conversation" trial, not a local one.

Direct trial contact for inquiries: clinicaltrials@totusmedicines.com Site to check: clinicaltrials.gov/study/NCT05683418

"I've begged for expanded access and compassionate use more times than I can count, and I've never had it granted. What I hear back is that any serious side effect or death off-protocol could jeopardise the main trial and the company's whole investment. It's heartbreaking as a patient, but it explains why even promising drugs like this rarely have an easy 'back door' for those of us who can't get into the formal trial." — Group member, living with metastatic HR+/HER2- breast cancer

ReDiscover-2 / Zovegalisib (NCT06982521) — Confirmed Locked Out, But Worth an Exception Request

This is the larger, later-stage Phase 3 trial, testing zovegalisib (RLY-2608), another mutant-selective PI3Kα inhibitor, against capivasertib itself, with interim data reporting 11.1 months median progression-free survival. It has its own page here: ReDiscover-2 (NCT06982521).

If you know someone who is failing options discussed on the CDK4/6 Options and Supplement Considerations page, this appears to be the best step forward over taking capivasertib or alpelisib first and being locked out.

Why it's still worth a letter: this trial does have UK sites — Bath, three London hospitals (St. Bartholomew's, UCLH, Sarah Cannon), Manchester (The Christie), and Truro — plus Victorian sites in Australia. A large, well-resourced Phase 3 program with this much site infrastructure is exactly the kind of trial where a documented pattern of exception requests could eventually prompt a protocol amendment or a parallel cohort. This is the trial where the template letter below is most directly applicable — not because you're likely to get a yes today, but because raising the question with a trial this size and this well-funded is how these criteria shift over time.

Site to check: rediscover2.com Direct trial contact for inquiries: ClinicalTrials@relaytx.com

"On paper this looks like the obvious next step after CDK4/6. In practice, it's brutally competitive. My oncologist technically has the trial 'open' at our centre, but he hasn't been given any patient spots at all. So we list it in my notes as an option that, for now, doesn't actually exist for me." — Group member, HR+/HER2- metastatic breast cancer

SNV4818 (NCT06736704) — Promising but Still Phase 1/2

This drug just had Novartis pay up to $3 billion to acquire the program, on the explicit bet that sparing wild-type PI3Kα is what finally lets patients stay on treatment long enough for it to matter. It's currently in Phase 1/2, and public sources confirm it is designed to selectively target PI3Kα mutations in breast cancer while sparing wild-type PI3Kα, with sites in Canada and Australia.

Site to check: clinicaltrials.gov/study/NCT06736704

What This Means, Practically

• If you're in the US or willing/able to travel there or to Spain, and you have HR+/HER2- breast cancer with prior AKT/PI3K/mTOR intolerance: TOS-358 is your most concrete, evidence-backed option. Confirm current site capacity and your other eligibility criteria (organ function, prior treatment lines, confirmed PIK3CA mutation) before assuming enrollment.

• If you're in the UK or Australia and want to stay closer to home: ReDiscover-2 has real, open sites near you, but you will need to actively request an exception to the standard exclusion criteria — this is not a case of just applying and hoping.

• If you're specifically interested in SNV4818: it sounds promising, but being a Phase 1/2 treatment, treat it as "ask before you assume" — reach out to the trial team directly to get the full picture before relying on secondhand summaries, including this one.

"When you add up all the slots across these next-generation PI3K trials, it's shockingly small compared to how many of us are out here needing them. The good ones are especially competitive. It really is a zero-sum game: if someone else gets a place, it means another person doesn't — and often there's no second-best option in the same class."

A Template You Can Send

If you were intolerant of (rather than non-responsive to) a PI3K/AKT/mTOR pathway inhibitor and are looking into a mutant-selective trial in this class, you can send something like this directly to a trial's medical information contact, or bring it to your oncologist or their nurse to pass along between visits:

Subject: Inquiry Regarding Expanded Access / Compassionate Use — [Trial Name/NCT Number]

Dear [Trial Medical Information Team / Principal Investigator],

My name is [Name], and I am a patient with [HR+/HER2- metastatic breast cancer, PIK3CA-mutant / relevant details]. I was treated with [capivasertib / other pathway inhibitor] from [dates], but was required to discontinue due to [severe hyperglycemia / specific intolerance — be specific, e.g. "fasting glucose exceeding 20 mmol/L requiring hospitalization" or "Grade 3 rash"], not due to disease progression on the drug.

I understand that [Trial Name, NCT number] currently excludes patients with prior exposure to PI3K, AKT, or mTOR inhibitors. I am writing to ask:

• Is there any expanded access, compassionate use, or parallel single-arm cohort available for patients who were intolerant of — rather than non-responsive to — a prior agent in this class?

• If not currently, is this a population your clinical team is considering for future trial design or amendment?

• Are there other trials in your portfolio, or ones you're aware of, that specifically welcome patients with prior AKT/PI3K inhibitor intolerance?

I am asking not only for myself but on behalf of a wider community of patients who share this exact situation. We would be very grateful for any guidance you can offer, and are happy to provide further clinical detail through my treating oncologist, [Oncologist name, contact], if helpful.

Thank you for your time and for the work your team is doing in this space.

With hope and respect, [Your name] [City, Country] [Contact details]

Before You Write

"I've written to multiple trial teams over the years, with letters from oncologists attached, clear documentation of severe toxicity, and still been told 'no'. It's demoralising, but I keep going because every 'no' is also data — it shows exactly where the system is failing patients who were intolerant, not non-responsive. If enough of us keep asking the same question, someone eventually has to redesign the trial to answer it." — Group member, HR+/HER2- metastatic breast cancer

Why This Matters Beyond One Email

One email might not change a trial's eligibility criteria. But a pattern of emails — from patients, from advocacy groups, from oncologists raising it in tumor boards and at conferences — is exactly how eligibility criteria do eventually shift. It has happened before in this field. Trials get amended. Expanded access programs get created when enough voices ask the same question.

The fact that one of these three trials (TOS-358) already has genuinely open eligibility for exactly this population shows the field is capable of designing around this problem — it's not a solved problem everywhere yet, but it's a solvable one, and it's already being solved in at least one place. For a broader look at how the trial landscape keeps shifting drug-by-drug in this same disease space, see New BCL-2 Inhibitor Trial in HR+ MBC – and Why Whack-a-Mole Still Matters.

If this is your story, or the story of someone in this group, please don't sit with it quietly. Send the email. Ask your oncologist to ask. Post here if you get an answer — good or bad — so we can build a shared map of what's actually possible right now, not just what the official trial listings say on paper.

"It's hard not to feel like all this writing and asking goes into a void. I honestly don't expect a single email from me to change anything — but I keep doing it because if nobody pushes back, the same exclusion rules just roll on to the next generation of trials untouched." — Group member, HR+/HER2- metastatic breast cancer

Trial sponsors respond to demand signals — from oncologists asking about expanded access, from patient advocacy groups raising the issue publicly, from patients themselves emailing and asking the question out loud. The squeaky wheel really does get the oil in this system, and right now, this particular wheel has been silent for too long.

Where Gedatolisib Fits In Right Now

Gedatolisib (Revtorpyk) is a newly approved intravenous drug that also targets the PI3K/AKT/mTOR pathway, used with fulvestrant, with or without palbociclib, for HR+/HER2- metastatic breast cancer without a PIK3CA mutation after progression on endocrine therapy. Trial data show little clinically significant hyperglycemia compared with older agents in this pathway, but st