Gynecological Cancer Patients with Specific Wnt Mutations and High DKK1 Levels Respond Better to DKN-01, Trial Results Show

Leap Therapeutics’s investigational therapy DKN-01, alone or in combination with Taxol (paclitaxel), leads to significantly better responses in women with relapsed endometrial or ovarian cancer whose tumors have high levels of the Dickkopf-1 (DKK1) protein, or specific mutations in the Wnt signaling pathway, according to results of a Phase 2 clinical trial.

Those findings highlight that the presence of active Wnt mutations and DKK1 levels may predict the effectiveness of DKN-01 in these patients.

The trial results were shown in oral and poster presentations at the 2019 Annual Global Meeting of the International Gynecologic Cancer Society, held on Sept. 19–21 in Rio de Janeiro, Brazil.

Wnt is an essential signaling pathway during embryonic development, but it is not active in most adult cells. Some Wnt mutations can reactivate the pathway, leading to high levels of DDK1 (a Wnt regulator), which are associated with uncontrolled cell growth and suppression of the immune response.

High levels of DDK1, found in several types of cancer, are associated with more aggressive disease and poorer outcomes.

DKN-01 is an immunotherapy that specifically targets DKK1, resulting in a dual effect of cancer cell death and a boost of the immune response against the tumor. DKN-01 is designed to work alone and in combination with chemotherapies and immunotherapies.

The ongoing Phase 2 clinical trial (NCT03395080) is evaluating the safety and effectiveness of DKN-01 as a single therapy, or in combination with Taxol chemotherapy, in women with relapsed or refractory epithelial endometrial cancer (EEC), epithelial ovarian cancer (EOC), or uterine or ovarian carcinosarcoma.

The six-month trial’s primary goals are the assessment of objective response rate (ORR) — the proportion of patients showing a reduction in tumor burden — and treatment-associated adverse events (side effects).

Additional goals include the assessment of overall survival, progression-free survival (PFS) — the time a patient lived without signs of disease progression — and potential associations between treatment response and the presence of Wnt-activating mutations and levels of DKK1.

So far, 92 women with relapsed endometrial or ovarian cancer have been enrolled and assigned randomly to receive 300 mg of DKN-01 either alone (45 women) or in combination with 80 mg of Taxol (47 women) in 28-day cycles.

In each group, approximately 50% of patients were required to have mutations in the Wnt pathway, including Wnt activating mutations.

By July 30 (the data cut-off date), women in the single therapy group have received a median of two cycles, and those in the combo therapy group have received a median of four cycles.

Partial responses were only achieved by three women with relapsed endometrial cancer — two in the single therapy group and one in the combination therapy group.

After the cut-off date, a woman with relapsed endometrial cancer who showed a partial tumor reduction after eight cycles of DKN-01 single therapy was reported to have a complete response after 14 cycles (14 months of treatment).

A total of 88 women had genetic data on the presence (21 women) or absence (67 women) of Wnt-activating mutations, while 54 women had their DDK1 levels measured, with 13 showing high DDK1 levels.

DKN-01 treatment significantly prolonged the PFS (by more than twofold) in women with Wnt-activating mutations or high levels of DKK-01, compared to those without these features, regardless of therapy and cancer type.

While average overall survival has not been reached yet for women with Wnt-activating mutations or high DKK1 levels, preliminary results suggest a trend toward longer overall survival, compared to women without these features.

Among women without Wnt-activating mutations or high DDK1 levels, 27% and 29% had died by 321 and 365 days of treatment, respectively. After 400 days of treatment, about 85% of the women who had any of these tumor biomarkers are still alive.

The results also showed that DKK-01 was well-tolerated as a single therapy and in combination with Taxol.

“We are very enthusiastic about the single agent and combination activity of DKN-01 observed in this heavily pre-treated patient population,” Rebecca C. Arend, MD, who presented the data at the meeting, said in a press release.

“A monotherapy complete response and the correlation of patient outcomes with prevalent tumor biomarkers are impressive signals of activity in these patients, who have poor prognosis and few treatment options,” Arend saidd.

Patient follow-up is ongoing, and additional data is expected in the first half of 2020.

The company also is investigating DKK-01, alone or in combination with Keytruda (pembrolizumab), in people with esophageal cancer in an ongoing Phase 1 clinical trial (NCT02013154), which has shown positive preliminary results.